Mechanisms of Hormone Action

A hormone is a secreted chemical messenger that enables the communication between cells and tissues throughout the body.

A hormone is a chemical messenger that enables the communication between cells. Hormones are secreted by the glands of the endocrine system and they serve to maintain homeostasis and to regulate numerous other systems and processes, including reproduction and development.

Hormone Signaling

The glands of the endocrine system secrete hormones directly into the extracellular environment. The hormones then diffuse to the bloodstream via capillaries and are transported to the target cells through the circulatory system. This allows hormones to affect tissues and organs far from the site of production or to apply systemic effects to the whole body.

Hormone-producing cells are typically specialized and reside within a particular endocrine gland, such as thyrocytes in the thyroid gland. Hormones exit their cell of origin through the process of exocytosis or by other means of membrane transport.

Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues. This is so in the case of insulin, which triggers a diverse range of systemic physiological effects. Different tissue types may also respond differently to the same hormonal signal. As a result, hormonal signaling is elaborate and hard to dissect.

Hormones activate target cells by diffusing through the plasma membrane of the target cells (lipid-soluble hormones) to bind a receptor protein within the cytoplasm of the cell, or by binding a specific receptor protein in the cell membrane of the target cell (water-soluble proteins). In both cases, the hormone complex will activate a chain of molecular events within the cell that will result in the activation of gene expression in the nucleus.

The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback loop.

Steps of Hormonal Signaling

• Biosynthesis of a particular hormone in a particular tissue.
• Storage and secretion of the hormone.
• Transport of the hormone to the target cells, tissues, or organs.
• Recognition of the hormone by an associated cell membrane or an intracellular receptor protein.
• Relay and amplification of the received hormonal signal via a signal transduction process.
• Potential feedback to a hormone-producing cell.

Hormone Classes

Hormones are typically divided into three classes:

Peptide: Hormones that are modified amino acids or short (peptide) or long (protein) chains of amino acids. Additionally, they can contain carbohydrate moieties.

Lipid: Steroid hormones that contain lipids synthesized from cholesterol and eicosanoids that contain lipids synthesized from the fatty acid chains of phospholipids found in the plasma membrane.

Monoamine: Hormones derived from aromatic amino acids such as
phenylalanine, tyrosine, and tryptophan.

Hormone Receptors

Hormones activate a cellular response in the target cell by binding to a specific receptor in the target cell.

A hormone receptor is a molecule that binds to a specific hormone. Receptors for peptide hormones tend to be found on the plasma membrane of cells, whereas receptors for lipid-soluble hormones are usually found within the cytoplasm.

Upon hormone binding, the receptor can initiate multiple signaling pathways that ultimately lead to changes in the behavior of the target cells.

The hormone activity within a target cell is dependent on the effective concentration of hormone-receptor complexes that are formed. The number of these complexes is in turn regulated by the number of hormone or receptor molecules available, and the binding affinity between hormone and receptor.

Lipophobic Hormones

Many hormones are composed of polypeptides—such as thyroid-stimulating hormones, follicle-stimulating hormones, luteinizing hormones, and insulin. These molecules are not lipid-soluble and therefore cannot diffuse through cell membranes.

The receptors for these hormones need to be localized to the cells’ plasma membranes. Following an interaction with the hormones, a cascade of secondary effects within the cytoplasm of the cell is triggered, often involving the addition or removal of phosphate groups to cytoplasmic proteins, changes in ion channel permeability, or an increase in the concentrations of intracellular molecules that may act as secondary messengers, such as cyclic AMP.

Lipophilic Hormones

Lipophilic hormones—such as steroid or thyroid hormones—are able to pass through the cell and nuclear membrane; therefore receptors for these hormones do not need to be, although they sometimes are, located in the cell membrane.

The majority of lipophilic hormone receptors are transcription factors that are either located in the cytosol and move to the cell nucleus upon activation or remain in the nucleus waiting for the steroid hormone to enter and activate them.
Upon binding by the hormone the receptor undergoes a conformational change, and the receptor together with the bound hormone influence transcription, either alone or in association with other transcription factors.

Chemistry of Hormones

There are three classes of hormones: peptide hormones, lipid hormones, and monoamine hormones.

A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism.

There are three classes of hormones:

1. Peptide hormones
2. Lipid-derived hormones
3. Monoamine hormones

Peptide Hormones

Peptide hormones consist of short chains of amino acids, such as vasopressin, that are secreted by the pituitary gland and regulate osmotic balance; or long chains, such as insulin, that are secreted by the pancreas, which regulates glucose metabolism.

Some peptide hormones contain carbohydrate side chains and are termed glycoproteins, such as the follicle-stimulating hormone. All peptide hormones are hydrophilic and are therefore unable to cross the plasma membrane alone.

Lipid-Derived Hormones

Lipid and phospholipid-derived hormones are produced from lipids such as linoleic acid and arachidonic acid. Steroid hormones, which form the majority of lipid hormones, are derived from carbohydrates; for example, testosterone is produced primarily in the testes and plays a key role in the development of the male reproductive system.

Eicosanoids are also lipid hormones that are derived from fatty acids in the plasma membrane. Unlike other hormones, eicosanoids are not stored in the cell—they are synthesized as required. Both are lipophilic and can cross the plasma membrane.

Monoamine Hormones

Monoamine hormones are derived from single aromatic amino acids like phenylalanine, tyrosine, and tryptophan. For example, the tryptophan-derived melatonin that is secreted by the pineal gland regulates sleep patterns.

Transport of Hormones

Hormones synthesized by the endocrine glands are transported throughout the body by the bloodstream.

The endocrine system is a system of ductless glands that secrete hormones directly into the circulatory system to be carried long distances to other target organs that regulate key body and organ functions.

Some endocrine glands secrete into a portal system rather than the systemic circulation that allows for the direct targeting of hormones. For example, hormones secreted by the pancreas pass into the hepatic portal vein that transports them directly to the liver.

Once within the circulatory system, a small proportion of hormones circulate freely, however, the majority are bound with a transport protein. Mainly produced in the liver, these transport proteins are hormone specific, such as the sex hormone-binding globulin that binds with the sex hormones.

When bound with a transport protein hormones are typically inactive, and their release is often triggered in regions of low hormone concentration or can be controlled by other factors. Therefore, transport proteins can act as a reservoir within the circulatory system and help ensure an even distribution of hormones within an organ or tissue.

The endocrine system is a system of ductless glands that secrete hormones—chemical messengers that are carried for long distances.

The Endocrine System

The endocrine system is a system of ductless glands that secretes hormones directly into the circulatory system to be carried long distances to other target organs regulating key body and organ functions. For example, the pineal gland, located at the base of the brain, secretes the hormone melatonin, responsible for regulating sleep patterns.

Endocrine glands are typically well vascularized and the cells comprising the tissue are typically rich in intracellular vacuoles or granules that store hormones prior to release. Endocrine signaling is typically slow to initiate but is prolonged in response; this provides a counterpoint to the more rapid and short-lived nervous system signals.

The endocrine system is in contrast to the exocrine system, which features ducted glands that secrete substances onto an epithelial surface; for example, a sweat gland. Additionally, the endocrine system is differentiated from shorter distance signaling such as autocrine (a cell affecting itself), juxtacrine (a cell affecting its direct neighbors), and paracrine (a cell affecting other nearby cells) signaling.

Key Endocrine Glands

The major endocrine glands include the pituitary, pineal, ovaries, testes, thyroid, hypothalamus and adrenal glands, additionally other tissues such as the kidney and liver also display secondary adrenal functions.

Comparing the Nervous and Endocrine Systems

The nervous system and endocrine system both use chemical messengers to signal cells, but each has a different transmission speed.

The body must maintain a constant internal environment, through a process termed homeostasis, while also being able to respond and adapt to external events. The nervous and endocrine systems both work to bring about this adaptation, but their response patterns are different. The nervous system and the endocrine system use chemical messengers to signal cells, but the speed at which these messages are transmitted and the length of their effects differs.

Nervous System

The nervous system responds rapidly to stimuli by sending electrical action potentials along neurons, which in turn transmit these action potentials to their target cells using neurotransmitters, the chemical messenger of the nervous system. The response to stimuli by the nervous system is near-instantaneous, although the effects are often short-lived. An example is the recoil mechanism of an arm when touching something hot.

Endocrine System

The endocrine system relies on hormones to elicit responses from target cells. These hormones are synthesized in specialized glands at a distance from their target and travel through the bloodstream or inter-cellular fluid. Upon reaching their target, hormones can induce cellular responses at a protein or genetic level.

This process takes significantly longer than that of the nervous system, as endocrine hormones must first be synthesized, transported to their target cell, and enter or signal the cell. However, although hormones act more slowly than a nervous impulse, their effects are typically longer lasting.

Additionally, the target cells can respond to minute quantities of hormones and are sensitive to subtle changes in hormone concentration. For example, the growth hormones secreted by the pituitary gland are responsible for sustained growth during childhood.

The hypothalamic hormones are released into blood vessels that connect the hypothalamus and the pituitary gland (i.e., the hypothalamic-hypophyseal portal system). Because they generally promote or inhibit the release of hormones from the pituitary gland, hypothalamic hormones are commonly called releasing or inhibiting hormones. The major releasing and inhibiting hormones include the following

• Corticotropin-releasing hormone (CRH) – which is part of the hormone system regulating carbohydrate, protein, and fat metabolism as well as sodium and water balance in the body

• Gonadotropin-releasing hormone (GnRH), which helps control sexual and reproductive functions, including pregnancy and lactation (i.e., milk production)

• Thyrotropin-releasing hormone (TRH), which is part of the hormone system controlling the metabolic processes of all cells and which contributes to the hormonal regulation of lactation

• Growth hormone-releasing hormone (GHRH), which is an essential component of the system promoting the organism’s growth

• Somatostatin, which also affects bone and muscle growth but has the opposite effect as that of GHRH

• Dopamine, a substance that functions primarily as a neurotransmitter but also has some hormonal effects, such as repressing lactation until it is needed after childbirth.

THE MAIN HORMONE-PRODUCING GLANDS ARE:

• Hypothalamus: The hypothalamus is responsible for body temperature, hunger, moods, and the release of hormones from other glands; and also controls thirst, sleep, and sex drive.
• Pituitary: Considered the “master control gland,” the pituitary gland controls other glands and makes the hormones that trigger growth.
• Parathyroid: This gland controls the amount of calcium in the body.
• Pancreas: This gland produces insulin that helps control blood sugar levels
• Thyroid: The thyroid produces hormones associated with calorie burning and heart rate.
• Adrenal: Adrenal glands produce the hormones that control sex drive and cortisol, the stress hormone.
• Pineal: This gland produces melatonin which affects sleep.
• Ovaries: Only in women, the ovaries secrete estrogen, testosterone, and progesterone, the female sex hormones.
• Testes: Only in men, the testes produce the male sex hormone, testosterone, and produce sperm.

References

Cholinergic Neurons and Receptors

Acetylcholine is a neurotransmitter in the central and peripheral nervous systems that affect plasticity, arousal, and reward.

Acetylcholine

Acetylcholine (ACh) is an organic, polyatomic ion that acts as a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms, including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS) and the only neurotransmitter used in the motor division of the somatic nervous system (sensory neurons use glutamate and various peptides at their synapses ).

Acetylcholine is also the principal neurotransmitter in all autonomic ganglia. In cardiac tissue, acetylcholine neurotransmission has an inhibitory effect, which lowers heart rate. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle.

 

Acetylcholine: The chemical structure of acetylcholine is depicted.

Acetylcholine was first identified in 1914 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name Vagusstoff because it was released from the vagus nerve. They jointly received the 1936 Nobel Prize in physiology or medicine for their work. Acetylcholine was also the first neurotransmitter to be identified.

Functions

 

Muscarinic acetylcholine receptor M2: This human M2 muscarinic acetylcholine receptor is bound to an antagonist (ACh).

Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central nervous system (CNS) as a neuromodulator. In the peripheral nervous system, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. In the central nervous system, acetylcholine and its associated neurons form the cholinergic system.

When acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand-gated sodium channels in the cell membrane. Sodium ions then enter the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Although acetylcholine induces the contraction of skeletal muscle, it acts via a different type of receptor to inhibit the contraction of cardiac muscle fibers.

In the autonomic nervous system, acetylcholine is released in the following sites: all pre-and post-ganglionic parasympathetic neurons, all pre-ganglionic sympathetic neurons, some post-ganglionic sympathetic fibers, and in the pseudo motor neurons to sweat glands.

In the central nervous system, ACh has a variety of effects as a neuromodulator for plasticity, arousal, and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up and in sustaining attention.

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer’s disease. ACh has also been shown to promote REM sleep.

In the cerebral cortex, tonic ACh inhibits layer 4 neurons, the main targets of thalamocortical inputs while exciting pyramidal cells in layers 2/3 and 5. This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer 5 excitatory microcircuits.

As a result, these layer-specific effects of ACh might function to improve the signal-to-noise ratio of cortical processing. At the same time, acetylcholine acts through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex that further dampen cortical activity.

 

Nicotinic acetylcholine receptors: These schematics describe the heteromeric and homomeric nature of nAChRs. The heteromeric receptors found in the central nervous system are made up of 2 α and 3 β subunits with the binding site at the interface of α and adjacent subunits. Homomeric receptors contain 5 identical subunits and have 5 binding sites located at the interfaces between adjacent subunits.

One well-supported function of ACh in the cortex is increased responsiveness to sensory stimuli, a form of attention. Phasic increases of ACh during visual, auditory, and somatosensory stimulus presentations have been found to increase the firing rate of neurons in the corresponding primary sensory cortices.

When cholinergic neurons in the basal forebrain are lesioned, animals’ ability to detect visual signals was robustly and persistently impaired. In that same study, an animals’ ability to correctly reject non-target trials was not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli.

ACh has been implicated in reporting expected uncertainty in the environment, based both on the suggested functions listed above and results recorded while subjects perform a behavioral cuing task. Reaction time differences between correctly cued trials and incorrectly cued trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically and surgically altered levels of ACh. The result was also found in Alzheimer’s disease patients and smokers after nicotine (an ACh agonist) consumption.

Creation of ACh

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh.

An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain. The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function.

Certain neurotoxins work by inhibiting acetylcholinesterase, leading to excess acetylcholine at the neuromuscular junction. This results in paralysis of the muscles needed for breathing and stops the beating of the heart.

Adrenergic Neurons and Receptors

Adrenergic receptors are molecules that bind catecholamines. Their activation leads to overall stimulatory and sympathomimetic responses.

The adrenergic receptors (or adrenoceptors) are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine or noradrenaline, and epinephrine ( adrenaline ). Although dopamine is a catecholamine, its receptors are in a different category.

Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic (or sympathomimetic) response (e.g., the fight-or-flight response). For instance, the heart rate will increase, pupils will dilate, energy will be mobilized, and blood flow will be diverted from non-essential organs to skeletal muscle.

 

Adrenaline (epinephrine): The 2D structure of adrenaline (epinephrine) is illustrated.

 

Noradrenaline (norepinephrine): The 2D structure of noradrenaline (norepinephrine) is illustrated here.

There are two main groups of adrenergic receptors, α, and β, with several subtypes. α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi-coupled receptor). Phenylephrine is a selective agonist of the α receptor.

β-receptors have the subtypes β1, β2, and β3. All three are linked to Gs proteins (although β2 also couples to Gi), which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include the cAMP-dependent protein, kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a nonselective agonist.

Adrenaline or noradrenaline is a receptor-ligand to α1, α2, or β-adrenergic receptors (the pathway is shown in the following diagram).

• α1 couples to Gq, which results in increased intracellular Ca2+ that results in smooth muscle contraction.
• α2, on the other hand, couples to Gi, which causes a decrease of cAMP activity, that results in smooth muscle contraction.
• β receptors couple to Gs, and increases intracellular cAMP activity, resulting in heart muscle contraction, smooth muscle relaxation, and glycogenolysis.

 

Adrenergic signal transduction: This schematic shows the mechanism of adrenergic receptors. Adrenaline and noradrenaline are ligands to α1, α2, or β-adrenergic receptors. α1-receptors couple to Gq, resulting in increased intracellular Ca2+ and causing smooth muscle contraction. α2 receptors couple to Gi, causing a decrease in cAMP activity and resulting in smooth muscle contraction. β-receptors couple to Gs, increasing intracellular cAMP activity and resulting in heart muscle contraction, smooth muscle relaxation, and glycogenolysis.

Adrenaline (epinephrine) reacts with both α- and β-adrenoceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoceptor stimulation dominates, producing overall vasodilation.

Smooth muscle behavior is variable depending on anatomical location. One important note is the differential effects of increased cAMP in smooth muscle compared to cardiac muscle. Increased cAMP will promote relaxation in smooth muscle while promoting increased contractility and pulse rate in cardiac muscle.

α-receptors have several functions in common, but also individual effects. Common (or still unspecified) effects include: vasoconstriction of cardiac arteries (coronary artery), vasoconstriction of veins, and decreased motility of smooth muscle in the gastrointestinal tract.

α1-adrenergic receptors are members of the G protein-coupled receptor superfamily. On activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC).

The PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of the endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell. This triggers all other effects.

Specific actions of the α1-receptor mainly involve smooth muscle contraction. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney (renal artery), and brain. Other areas of smooth muscle contraction are:

• Ureter.
• Vas deferens.
• Hair (arrector pili muscles).
• Uterus (when pregnant).
• Urethral sphincter.
• Bronchioles (although minor to the relaxing effect of β2 receptor on bronchioles).
• Blood vessels of the ciliary body (stimulation causes mydriasis).

Further effects include glycogenolysis and gluconeogenesis from adipose tissue and the liver, as well as secretion from sweat glands, and Na+ reabsorption from the kidney. Antagonists may be used in hypertension.

There are 3 highly homologous subtypes of α2 receptors: α2A, α2Β, and α2C.

α2-Receptor Effects

• Inhibition of insulin release in the pancreas.
• Induction of glucagon release from the pancreas.
• Contraction of sphincters of the gastrointestinal tract.
• Negative feedback in the neuronal synapses—presynaptic inhibition of noradrenaline release in CNS.

β1-Receptor Effects

• Increases cardiac output, by raising heart rate (positive chronotropic effect), increasing impulse conduction (positive dromotropic effect), and increasing contraction (positive inotropic effect), thus increasing the volume expelled with each beat (increased ejection fraction).
• Increases renin secretion from the juxtaglomerular cells of the kidney.
• Increases ghrelin secretion from the stomach.

β2-Receptor Effects

• Smooths muscle relaxation, e.g., in bronchi and the GI tract (decreased motility).
• Lipolysis in adipose tissue.
• Anabolism in skeletal muscle.
• Relaxes a non-pregnant uterus.
• Dilates arteries to skeletal muscle.
• Glycogenolysis and gluconeogenesis.
• Stimulates insulin secretion.
• Contracts the sphincters of the GI tract.
• Thickens secretions from the salivary glands.
• Inhibits histamine release from mast cells.
• Increases renin secretion from the kidney.
• Relaxation of bronchioles (salbutamol, a beta-2 agonist, relieves bronchiole constriction).

Agonists, Antagonists, and Drugs

Drugs affecting cholinergic neurotransmission may block, hinder, or mimic the action of acetylcholine and alter post-synaptic transmission.

Blocking, hindering, or mimicking the action of acetylcholine has many uses in medicine. Drugs that act on the acetylcholine system are either agonists to the receptors that stimulate the system, or antagonists that inhibit it.

Acetylcholine receptor agonists and antagonists can have a direct effect on the receptors or exert their effects indirectly. For example, by affecting the enzyme acetylcholinesterase the receptor-ligand is degraded. Agonists increase the level of receptor activation, antagonists reduce it.

Acetylcholine in the ANS

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes.

Muscarinic receptors are coupled to the G_i-protein; therefore, vagal activation decreases cAMP. G_i-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.

Increases in vagal activity to the SA node decrease the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential and decreasing heart rate. By hyperpolarizing the cells, vagal activation increases the cell’s threshold for firing, which contributes to the reduction of the firing rate.

Similar electrophysiological effects also occur at the atrioventricular AV node. However, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node. In the resting state, there is a large degree of vagal tone on the heart, which is responsible for low, resting heart rates.

There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.

Muscarinic Antagonists

 

Atropine: The 2D chemical structure of atropine is illustrated here.

Muscarinic receptor antagonists bind to muscarinic receptors, thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade (Atropa belladonna), Jimson weed (Datura stramonium), mandrake (Mandragora officinarum), and other plants of the family Solanaceae. Atropine’s pharmacological effects are due to its ability to bind to muscarinic acetylcholine receptors. It is an anti-muscarinic agent.

Working as a nonselective muscarinic acetylcholinergic antagonist, atropine increases firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions. In overdoses, atropine is poisonous.

Nicotinic Agonists

A nicotinic agonist is a drug that mimics, in one way or another, the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). Nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous system, and skeletal muscles.

They are ligand-gated ion channels with binding sites for acetylcholine as well as other agonists. When agonists bind to a receptor it stabilizes the open state of the ion channel allowing an influx of cations.

 

Nicotinic acetylcholine receptors: NAchR are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction.

The development of nicotinic acetylcholine receptor agonists began in the early nineties after the discovery of nicotine’s positive effects on animal memory. Nicotinic antagonists are mainly used for peripheral muscle paralysis in surgery, the classical agent of this type being tubocurarine, but some centrally acting compounds such as bupropion, mecamylamine, and 18-methoxycoronaridine block nicotinic acetylcholine receptors in the brain and have been proposed for treating drug addiction.

The nicotinic acetylcholine receptor agonists are gaining increasing attention as drug candidates for multiple central nervous system disorders such as Alzheimer’s disease, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction. In 2009 there were at least five drugs on the market that affect the nicotinic acetylcholine receptors.

Most indirect-acting ACh receptor agonists work by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system.

They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying degradation; some have been used as nerve agents (sarin and VX nerve gas) or pesticides (organophosphates and carbamates). In clinical use, they are administered to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer’s disease (rivastigmine increases cholinergic activity in the brain).

Beta Receptor Antagonists

Beta-blockers (sometimes written as β-blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, or beta antagonists, are a class of drugs used for various indications. They are particularly used for the management of cardiac arrhythmias, cardiac protection after myocardial infarction (heart attack), and hypertension.

As beta-adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. Beta-blockers block the action of endogenous catecholamines —epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular—on β-adrenergic receptors, part of the sympathetic nervous system that mediates the fight-or-flight response.

Sympathetic Responses

The sympathetic division of the autonomic nervous system maintains internal organ homeostasis and initiates the stress response.

Sympathetic Nervous System Physiology

Alongside the other two components of the autonomic nervous system, the sympathetic nervous system aids in the control of most of the body’s internal organs. Stress—as in the hyperarousal of the flight-or-fight response—is thought to counteract the parasympathetic system, which generally works to promote maintenance of the body at rest.

Sympathetic nervous system: The sympathetic nervous system extends from the thoracic to lumbar vertebrae and has connections with the thoracic, abdominal aortic, and pelvic plexuses.

The sympathetic nervous system is responsible for regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system and provide physiological regulation over diverse body processes including pupil diameter, gut motility (movement), and urinary output.

The SNS is perhaps best known for mediating the neuronal and hormonal stress response commonly known as the fight-or-flight response, also known as the sympathoadrenal response of the body. This occurs as the preganglionic sympathetic fibers that end in the adrenal medulla secrete acetylcholine, which activates the secretion of adrenaline (epinephrine), and to a lesser extent noradrenaline (norepinephrine).

Therefore, this response is mediated directly via impulses transmitted through the sympathetic nervous system, and also indirectly via catecholamines that are secreted from the adrenal medulla, and acts primarily on the cardiovascular system.

Messages travel through the SNS in a bidirectional flow. Efferent messages can trigger simultaneous changes in different parts of the body.

For example, the sympathetic nervous system can accelerate heart rate, widen bronchial passages, decrease motility of the large intestine, constrict blood vessels, increase peristalsis in the esophagus, cause pupillary dilation, piloerection (goosebumps) and perspiration (sweating), and raise blood pressure.

Afferent messages carry sensations such as heat, cold, or pain. Some evolutionary theorists suggest that the sympathetic nervous system operated in early organisms to maintain survival since the sympathetic nervous system is responsible for priming the body for action. One example of this priming is in the moments before waking, in which sympathetic outflow spontaneously increases in preparation for activity.

The Fight-or-Flight Response

The fight-or-flight response was first described by Walter Bradford Cannon. His theory states that animals react to threats with a general discharge of the sympathetic nervous system, priming the animal for fighting or fleeing. This response was later recognized as the first stage of a general adaptation syndrome that regulates stress responses among vertebrates and other organisms.

Catecholamine hormones, such as adrenaline or noradrenaline, facilitate the immediate physical reactions associated with a preparation for violent muscular action. These include the following:

• Acceleration of heart and lung action.
• Paling or flushing, or alternating between both.
• Inhibition of stomach and upper-intestinal action to the point where digestion slows down or stops.
• General effect on the sphincters of the body.
• Constriction of blood vessels in many parts of the body.
• Liberation of nutrients (particularly fat and glucose) for muscular action.
• Dilation of blood vessels for muscles.
• Inhibition of the lacrimal gland (responsible for tear production) and salivation.
• Dilation of the pupil (mydriasis).
• Relaxation of the bladder.
• Inhibition of erection.
• Auditory exclusion (loss of hearing).
• Tunnel vision (loss of peripheral vision).
• Disinhibition of spinal reflexes; and shaking.

In prehistoric times, the human fight-or-flight response manifested fight as aggressive, combative behavior and flight as fleeing potentially threatening situations, such as being confronted by a predator.

In current times, these responses persist, but fight-and-flight responses have assumed a wider range of behaviors. For example, the fight response may be manifested in angry, argumentative behavior, and the flight response may be manifested through social withdrawal, substance abuse, and even television viewing.

Males and females tend to deal with stressful situations differently. Males are more likely to respond to an emergency situation with aggression (fight), while females are more likely to flee (flight), turn to others for help, or attempt to defuse the situation (tend and befriend). During stressful times, a mother is especially likely to show protective responses toward her offspring and affiliate with others for shared social responses to threats.

Parasympathetic Responses

The parasympathetic nervous system regulates organ and gland functions during rest and is considered a slowly activated, dampening system.

The Parasympathetic Nervous System

Nerve innervation of the autonomic nervous system: The parasympathetic nervous system, shown in blue, is a division of the autonomic nervous system.

The parasympathetic nervous system (PSNS, or occasionally PNS) is one of the two main divisions of the autonomic nervous system (ANS). The autonomic nervous system (ANS, or visceral nervous system, or involuntary nervous system) is the part of the peripheral nervous system that acts as a control system, functioning largely below the level of consciousness and controlling visceral functions.

The ANS is responsible for regulating the internal organs and glands, which occurs unconsciously. Its roles include stimulation of rest-and-digest activities that occur when the body is at rest, including sexual arousal, salivation, lacrimation (tears), urination, digestion, and defecation.

Its action is described as being complementary to that of one of the other main branches of the ANS, the sympathetic nervous system, which is responsible for stimulating activities associated with the fight-or-flight response.

The sympathetic and parasympathetic divisions typically function in opposition to each other. This natural opposition is better understood as complementary in nature rather than antagonistic.

The sympathetic nervous system can be considered a quick response, mobilizing system; and the parasympathetic system is a more slowly activated, dampening system.

Parasympathetic Nervous System Functions

A useful acronym to summarize the functions of the parasympathetic nervous system is SLUDD (salivation, lacrimation, urination, digestion, and defecation). The parasympathetic nervous system may also be known as the parasympathetic division.

The parasympathetic nervous system uses chiefly acetylcholine (ACh) as its neurotransmitter, although peptides (such as cholecystokinin) may act on the PSNS as neurotransmitters. The ACh acts on two types of receptors, the muscarinic and nicotinic cholinergic receptors.

Most transmission occurs in two stages. When stimulated, the preganglionic nerve releases ACh at the ganglion, which acts on nicotinic receptors of the postganglionic neurons. The postganglionic nerve then releases ACh to stimulate the muscarinic receptors of the target organ.

Autonomic Interactions

The sympathetic and parasympathetic autonomic nervous systems cooperatively modulate internal physiology to maintain homeostasis.

Sympathetic and parasympathetic divisions typically function in opposition to each other. However, this opposition is better termed complementary in nature rather than antagonistic. For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake.

The sympathetic division typically functions in actions requiring quick responses. The parasympathetic division functions with actions that do not require immediate reaction. Consider sympathetic as fight or flight and parasympathetic as rest and digest or feed and breed.

The subdivisions of the autonomic nervous system: In the autonomic nervous system, preganglionic neurons connect the CNS to the ganglion.

However, many instances of sympathetic and parasympathetic activity cannot be ascribed to fight or rest situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in blood pressure if not for a compensatory increase in the arterial sympathetic tonus.

Another example is the constant, second-to-second modulation of heart rate by sympathetic and parasympathetic influences, as a function of the respiratory cycles. More generally, these two systems should be seen as permanently modulating vital functions, usually in an antagonistic fashion, to achieve homeostasis. Some typical actions of the sympathetic and parasympathetic systems are listed below.

The SNS promotes a fight-or-flight response, corresponds with arousal and energy generation, and performs the following functions:

• Inhibits digestion.
• Diverts blood flow away from the gastrointestinal (GI) tract and skin via vasoconstriction.
• Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1,200% in the case of skeletal muscles).
• Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange.
• Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for the enhanced blood flow to skeletal muscles.
• Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and far vision.
• Provides vasodilation for the coronary vessels of the heart.
• Constricts all the intestinal sphincters and the urinary sphincter.
• Inhibits peristalsis.
• Stimulates orgasm.

Conversely, the PSNS promotes a rest-and-digest response, and promotes the following functions:

• Dilates blood vessels leading to the GI tract, increasing blood flow.
• Constricts the bronchiolar diameter when the need for oxygen has diminished.
• Causes constriction of the pupil and contraction of the ciliary muscle to the lens, allowing for closer vision.
• Stimulates salivary gland secretion, and accelerates peristalsis.
• Stimulates sexual arousal.

Control of Autonomic Nervous System Function

The medulla oblongata, in the lower half of the brainstem, is the control center of the autonomic nervous system.

The autonomic nervous system (ANS) is the part of the peripheral nervous system that controls involuntary functions that are critical for survival. The ANS participates in the regulation of heart rate, digestion, respiratory rate, pupil dilation, and sexual arousal, among other bodily processes.

Within the brain, the ANS is located in the medulla oblongata in the lower brainstem. The medulla’s main functions are to control the cardiac, respiratory, and vasomotor centers, to mediate autonomic, involuntary functions, such as breathing, heart rate, and blood pressure, and to regulate reflex actions such as coughing, sneezing, vomiting, and swallowing.

The brain stem with pituitary and pineal glands: The medulla is a subregion of the brainstem and is a major control center for the autonomic nervous system.

The hypothalamus acts to integrate autonomic functions and receives autonomic regulatory feedback from the limbic system to do so. The ANS is classically divided into two subdivisions, the sympathetic division and the parasympathetic division.

The sympathetic division of the ANS is often referred to as the sympathetic nervous system (SNS). The SNS provides a noradrenergic drive to the ANS. It is often referred to as a quick response mobilizing system that initiates the body’s fight-or-flight response.

PSNS input to the ANS is responsible for the stimulation of feed-and-breed and rest-and-digest responses, as opposed to the fight-or-flight response initiated by the SNS. The parasympathetic division of the ANS (PSNS) acts to complement and modulate the drive provided by SNS neurotransmission within the ANS.

As a rule, the SNS functions in actions requiring quick responses while the PSNS is initiated in actions that don’t require an immediate response.

Innervation

Autonomic nerves travel to organs throughout the body. Most organs receive parasympathetic supply by the vagus nerve and sympathetic supply by splanchnic nerves. The sensory part of the latter reaches the spinal column at certain spinal segments. Pain in any internal organ is perceived as referred pain, more specifically as pain from the dermatome corresponding to the spinal segment.^[rx]

Preganglionic Neurons

In the autonomic nervous system (ANS), nerve fibers that connect the central nervous system to ganglia are known as preganglionic fibers.

Preganglionic Neuron Properties

In the autonomic nervous system (ANS), fibers from the central nervous system to the ganglion are known as preganglionic fibers. All preganglionic fibers, whether they are in the sympathetic nervous system (SNS) or in the parasympathetic nervous system (PSNS), are cholinergic—that is, these fibers use acetylcholine as their neurotransmitter—and are myelinated.

The ANS is unique in that it requires a sequential two-neuron efferent pathway; the preganglionic neuron must first cross a synapse onto a postganglionic neuron before innervating the target organ. The preganglionic, or first neuron will begin at the outflow and will cross a synapse at the postganglionic, or second neuron’s cell body. The postganglionic neuron will then cross a synapse at the target organ.

Sympathetic preganglionic fibers tend to be shorter than parasympathetic preganglionic fibers because sympathetic ganglia are often closer to the spinal cord while parasympathetic preganglionic fibers tend to project to and synapse with the postganglionic fiber close to the target organ.

Outflow Sites

Properties of the SNS and PSNS preganglionic neurons also differ with respect to the spinal cord exit points. The sympathetic division has thoracolumbar outflow, meaning that the neurons begin at the thoracic and lumbar (T1–L2) portions of the spinal cord. The parasympathetic division has craniosacral outflow, meaning that the neurons begin at the cranial nerves (CN3, CN7, CN9, CN10) and sacral (S2–S4) spinal cord.

The sympathetic division (thoracolumbar outflow) consists of cell bodies in the lateral horn of the spinal cord (intermediolateral cell columns) from T1 to L2. These cell bodies are GVE (general visceral efferent) neurons and are the preganglionic neurons. There are several locations where preganglionic neurons create synapses with their postganglionic neurons:

• The paravertebral ganglia of the sympathetic chain (these run on either side of the vertebral bodies), cervical ganglia, thoracic ganglia, rostral lumbar ganglia, caudal lumbar ganglia, and pelvic ganglia.
• The prevertebral ganglia celiac ganglion, aorticorenal ganglion, superior mesenteric ganglion, inferior mesenteric ganglion.
• The chromaffin cells of the adrenal medulla. This is the one exception to the two-neuron pathway rule: they create a synapse directly onto the target cell bodies.

The parasympathetic division (craniosacral outflow) consists of cell bodies from one of two locations: the brainstem (cranial nerves III, VII, IX, X) or the sacral spinal cord (S2, S3, S4).

These are the preganglionic neurons that synapse with the postganglionic neurons in these locations:

• Parasympathetic ganglia of the head (ciliary (CN III)).
• Submandibular (CN VII).
• Pterygopalatine (CN VII).
• Otic (CN IX)).
• In or near the wall of an organ innervated by the vagus (CN X) or sacral nerves (S2, S3, S4).

Divergence

Another major difference between the two ANS systems is divergence or the number of postsynaptic fibers a single preganglionic fiber creates a synapse with. Whereas in the parasympathetic division there is a divergence factor of roughly 1:4, in the sympathetic division there can be a divergence of up to 1:20.

The site of synapse formation and this divergence for both the sympathetic and parasympathetic preganglionic neurons do, however, occur within ganglia situated within the peripheral nervous system.

Autonomic Ganglia

Autonomic ganglia are clusters of neuron cell bodies that transmit sensory signals from the periphery to the integration centers in the CNS.

Autonomic ganglia are clusters of neuronal cell bodies and their dendrites. They are essentially a junction between autonomic nerves originating from the central nervous system and autonomic nerves innervating their target organs in the periphery.

The dorsal root ganglia lie along the vertebral column by the spine and develop in the embryo from neural crest cells, not neural tube. Therefore, the spinal ganglia can be regarded as a gray matter of the spinal cord that became translocated to the periphery.

The two main categories are sympathetic ganglia and parasympathetic ganglia. An example of a parasympathetic ganglion is the ciliary ganglion, involved in pupil constriction and accommodation. A depiction of all the parasympathetic ganglia in the head and neck is shown in the following illustration.

Dorsal Root Ganglia

A dorsal root ganglion (or spinal ganglion) is a nodule on a dorsal root of the spine that contains the cell bodies of nerve cells (neurons) that carry signals from the sensory organs towards the appropriate integration center.

Nerves that carry signals towards the brain are known as afferent nerves. The axons of dorsal root ganglion neurons are known as afferents. In the peripheral nervous system, afferents refer to the axons that relay sensory information into the central nervous system (i.e., the brain and the spinal cord).

These neurons are of the pseudo-unipolar type, meaning they have an axon with two branches that act as a single axon, often referred to as a distal process and a proximal process.

Unlike the majority of neurons found in the central nervous system, an action potential in a dorsal root ganglion neuron may initiate in the distal process in the periphery, bypass the cell body, and continue to propagate along the proximal process until reaching the synaptic terminal in the dorsal horn of the spinal cord.

The distal section of the axon may either be a bare nerve ending or encapsulated by a structure that helps relay specific information to a nerve. The nerve endings of dorsal root ganglion neurons have a variety of sensory receptors that are activated by mechanical, thermal, chemical, and noxious stimuli.

In these sensory neurons, a group of ion channels thought to be responsible for somatosensory transduction have been identified. For example, a Meissner’s corpuscle or Pacinian corpuscle may encapsulate the nerve ending, rendering the distal process sensitive to mechanical stimulation, such as stroking or vibration, respectively.

Sympathetic Ganglia

Sympathetic ganglia are the ganglia of the sympathetic nervous system. They deliver information to the body about stress and impending danger and are responsible for the familiar fight-or-flight response. They contain approximately 20,000–30,000 nerve cell bodies and are located close to and on either side of the spinal cord in long chains.

Sympathetic ganglia are the tissue from which neuroblastoma tumors arise. The bilaterally symmetric sympathetic chain ganglia —also called the paravertebral ganglia —are located just ventral and lateral to the spinal cord. The chain extends from the upper neck down to the coccyx, forming the unpaired coccygeal ganglion.

Preganglionic nerves from the spinal cord create a synapse end at one of the chain ganglia, and the postganglionic fiber extends to an effector, typically a visceral organ in the thoracic cavity. There are usually 21 or 23 pairs of these ganglia: three in the cervical region, 12 in the thoracic region, four in the lumbar region, four in the sacral region, and a single, unpaired ganglion lying in front of the coccyx called the ganglion impair.

Neurons of the collateral ganglia also called the prevertebral ganglia, receive input from the splanchnic nerves and innervate organs of the abdominal and pelvic region. These include the celiac ganglia, superior mesenteric ganglia, and inferior mesenteric ganglia.

Parasympathetic Ganglia

Parasympathetic ganglia are the autonomic ganglia of the parasympathetic nervous system. Most are small terminal ganglia or intramural ganglia, so named because they lie near or within (respectively) the organs they innervate. The exceptions are the four paired parasympathetic ganglia of the head and neck.

Efferent parasympathetic nerve signals are carried from the central nervous system to their targets by a system of two neurons. The first neuron in this pathway is referred to as the preganglionic or presynaptic neuron. Its cell body sits in the central nervous system and its axon usually extends to a ganglion somewhere else in the body, where it synapses with the dendrites of the second neuron in the chain.

This second neuron is referred to as the postganglionic or postsynaptic neuron. The axons of presynaptic parasympathetic neurons are usually long. They extend from the CNS into a ganglion that is either very close to or embedded in their target organ. As a result, the postsynaptic parasympathetic nerve fibers are very short.

Postganglionic Neurons

In the autonomic nervous system, fibers from the ganglion to the effector organ are called postganglionic fibers.

In the autonomic nervous system, fibers from the ganglion to the effector organ are called postganglionic fibers. The post-ganglionic neurons are directly responsible for changes in the activity of the target organ via biochemical modulation and neurotransmitter release.

The neurotransmitters used by postganglionic fibers differ. In the parasympathetic division, they are cholinergic and use acetylcholine as their neurotransmitter. In the sympathetic division, most are adrenergic, meaning they use norepinephrine as their neurotransmitter.

The Sympathetic Fibers

At the synapses within the ganglia, the preganglionic neurons release acetylcholine, a neurotransmitter that activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons—with two important exceptions—release norepinephrine, which activates adrenergic receptors on the peripheral target tissues. The activation of target tissue receptors causes the effects associated with the sympathetic system.

The two exceptions mentioned above are the postganglionic neurons of sweat glands and the chromaffin cells of the adrenal medulla. The postganglionic neurons of sweat glands release acetylcholine for the activation of muscarinic receptors. The chromaffin cells of the adrenal medulla are analogous to post-ganglionic neurons—the adrenal medulla develops in tandem with the sympathetic nervous system and acts as a modified sympathetic ganglion. Within this endocrine gland, the pre-ganglionic neurons create synapses with chromaffin cells and stimulate the chromaffin cells to release norepinephrine and epinephrine directly into the blood.

Presynaptic nerves’ axons terminate in either the paravertebral ganglia or prevertebral ganglia. In all cases, the axon enters the paravertebral ganglion at the level of its originating spinal nerve.

After this, it can then either create a synapse in this ganglion, ascend to a more superior ganglion, or descend to a more inferior paravertebral ganglion and make a synapse there, or it can descend to a prevertebral ganglion and create a synapse there with the postsynaptic cell. The postsynaptic cell then goes on to innervate the targeted end effector (i.e., gland, smooth muscle, etc.).

Because paravertebral and prevertebral ganglia are relatively close to the spinal cord, presynaptic neurons are generally much shorter than their postsynaptic counterparts, which must extend throughout the body to reach their destinations.

The Parasympathetic Fibers

The axons of presynaptic parasympathetic neurons are usually long. They extend from the CNS into a ganglion that is either very close to or embedded in their target organ. As a result, the postsynaptic parasympathetic nerve fibers are very short.

In the cranium, preganglionic fibers (cranial nerves III, VII, and IX) usually arise from specific nuclei in the central nervous system (CNS) and create a synapse at one of four parasympathetic ganglia: ciliary, pterygopalatine, otic, or submandibular.

From these four ganglia the postsynaptic fibers complete their journey to target tissues via cranial nerve V (the trigeminal ganglion with its ophthalmic, maxillary, and mandibular branches).

The vagus nerve does not participate in these cranial ganglia, as most of its fibers are destined for a broad array of ganglia on or near the thoracic viscera (esophagus, trachea, heart, lungs) and the abdominal viscera (stomach, pancreas, liver, kidneys). It travels all the way down to the midgut/hindgut junction, which occurs just before the splenic flexure of the transverse colon.

The pelvic splanchnic efferent preganglionic nerve cell bodies reside in the lateral gray horn of the spinal cord at the S2–S4 spinal levels. Their axons continue away from the CNS to synapse at an autonomic ganglion close to the organ of innervation. This differs from the sympathetic nervous system, where synapses between pre- and post-ganglionic efferent nerves in general occur at ganglia that are farther away from the target organ.

The parasympathetic nervous system uses acetylcholine (ACh) as its chief neurotransmitter, although peptides (such as cholecystokinin) may act on the PSNS as a neurotransmitter. The ACh acts on two types of receptors, the muscarinic and nicotinic cholinergic receptors.

Most transmissions occur in two stages: When stimulated, the preganglionic nerve releases ACh at the ganglion, which acts on the nicotinic receptors of the postganglionic neurons. The postganglionic nerve then releases ACh to stimulate the muscarinic receptors of the target organ.

Autonomic Plexuses

Autonomic plexuses are formed from sympathetic and parasympathetic fibers that innervate and regulate the overall activity of visceral organs.

Autonomic plexuses are formed from sympathetic postganglionic axons, parasympathetic preganglionic axons, and some visceral sensory axons. The nerves in each plexus are close to each other, as in the plexuses of the somatic nervous system, but typically do not interact or synpase together.

Sympathetic trunk: This section of the sympathetic trunk shows both the celiac and the hypogastric plexus.

Instead, they provide a complex innervation pattern to the target organs, since most organs are innervated by both divisions of the autonomic nervous system. The autonomic plexuses include the cardiac plexus, the pulmonary plexus, the esophageal plexus, and the abdominal aortic plexus, and the superior and inferior hypogastric plexuses.

Plexuses

Cardiac

The cardiac plexus is a plexus of nerves situated at the base of the heart that innervates the heart. The superficial part of the cardiac plexus lies beneath the arch of the aorta, in front of the right pulmonary artery. It is formed by the superior cardiac branch of the left sympathetic trunk and the lower superior cervical cardiac branch of the left vagus nerve. A small ganglion, the cardiac ganglion of Wrisberg, is occasionally found connected with these nerves at their point of junction.

Pulmonary

The pulmonary plexus is an autonomic plexus formed from pulmonary branches of vagus nerve and the sympathetic trunk. It supplies the bronchial tree and the visceral pleura.

Esophageal

The esophageal plexus is formed by nerve fibers from two sources: the branches of the vagus nerve and the visceral branches of the sympathetic trunk. The esophageal plexus and the cardiac plexus contain the same types of fibers and are both considered thoracic autonomic plexus(es).

Abdominal

The abdominal aortic plexus is formed by branches derived, on either side, from the celiac plexus and ganglia, and receives filaments from some of the lumbar ganglia. It is situated on the sides and front of the aorta, between the origins of the superior and inferior mesenteric arteries.

From this plexus arise parts of the spermatic, the inferior mesenteric, and the hypogastric plexuses; it also distributes filaments to the inferior vena cava.

Superior Hypogastric Plexus

The superior hypogastric plexus (in older texts, hypogastric plexus or presacral nerve) is a plexus of nerves situated on the vertebral bodies below the bifurcation of the abdominal aorta.

Inferior Hypogastric Plexus

The inferior hypogastric plexus (pelvic plexus in some texts) is a plexus of nerves that supplies the viscera of the pelvic cavity. The inferior hypogastric plexus is a paired structure, with each situated on the side of the rectum in the male, and at the sides of the rectum and vagina in the female.

Parasympathetic (Craniosacral) Division

Parasympathetic ganglia are the autonomic ganglia of the parasympathetic nervous system that lie near or within the organs they innervate.

Parasympathetic ganglia are the autonomic ganglia of the parasympathetic nervous system, blue fibers). Most are small terminal ganglia or intramural ganglia, so named because they lie near or within (respectively) the organs they innervate.

The exceptions are the four paired parasympathetic ganglia of the head and neck. These paired ganglia supply all parasympathetic innervation to the head and neck: ciliary ganglion (spincter pupillae, ciliary muscle), pterygopalatine ganglion (lacrimal gland, glands of nasal cavity), submandibular ganglion (submandibular and sublingual glands), and otic ganglion (parotid gland).

Nerve innervation of the autonomic nervous system: The parasympathetic nervous system, shown in blue, is a division of the autonomic nervous system.

Each has three roots entering the ganglion (motor, sympathetic, and sensory roots) and a variable number of exiting branches.

• The motor root carries presynaptic parasympathetic nerve fibers (general visceral efferent fibers) that terminate in the ganglion by creating a synapse for the postsynaptic fibers traveling to target organs.
• The sympathetic root carries postsynaptic sympathetic fibers (general visceral efferent fibers) that traverse the ganglion without creating a synapse.
• The sensory root carries general sensory fibers (general somatic afferent fibers) that also do not create a synapse in the ganglion.

Some ganglia also carry special sensory fibers (special visceral afferent) for taste sensation.

The nerves that supply parasympathetic fibers to the parasympathetic ganglia of the head include the oculomotor nerve (ciliary ganglion), the facial nerve (pterygopalatine ganglion, submandibular ganglion), the glossopharyngeal nerve (otic ganglion), the vagus nerve, and the pelvic splanchnic nerves.

Because of its location, the parasympathetic system is commonly referred to as having craniosacral outflow, in contrast to the sympathetic nervous system, which is said to have thoracolumbar outflow.

Sympathetic Nervous System

Sympathetic ganglia are the ganglia of the sympathetic nervous system that initiate fight-or-flight, stress-mediated responses.

Nerve innervation of the autonomic nervous system: The parasympathetic nervous system, shown in blue, is a division of the autonomic nervous system.

The sympathetic ganglia are the ganglia of the sympathetic nervous system (the red lines in the diagram below). They deliver information to the body about stress and impending danger and are responsible for the familiar fight-or-flight response.

This response is also known as the sympathetic-adrenal response because the pre-ganglionic sympathetic fibers that end in the adrenal medulla—like all sympathetic fibers—secrete acetylcholine. This secretion activates the secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine) from the adrenal medulla.

Therefore, this response is mediated directly via impulses transmitted through the sympathetic nervous system, and indirectly via catecholamines secreted from the adrenal medulla, and acts primarily on the cardiovascular system.

An example of a sympathetic ganglion in a thoracic nerve is shown in. ganglia contain approximately 20000–30000 nerve cell bodies and are located close to and on either side of the spinal cord in long chains. Sympathetic ganglia are the tissue from which neuroblastoma tumors arise.

The bilaterally symmetric sympathetic chain ganglia, also called the paravertebral ganglia, are located just ventral and lateral to the spinal cord. The chain extends from the upper neck down to the coccyx, forming the unpaired coccygeal ganglion.

Preganglionic nerves from the spinal cord create a synapse at one end of the chain ganglia and the postganglionic fiber extends to an effector, typically a visceral organ, in the thoracic cavity. There are usually 21 or 23 pairs of these ganglia: 3 in the cervical region, 12 in the thoracic region, 4 in the lumbar region, 4 in the sacral region, and a single, unpaired ganglion lying in front of the coccyx called the ganglion impair.

Neurons of the collateral ganglia also called the prevertebral ganglia, receive input from the splanchnic nerves and innervate organs of the abdominal and pelvic region. These include the celiac ganglia, the superior mesenteric ganglia, and the inferior mesenteric ganglia.

The sympathetic nervous system is said to have thoracolumbar outflow based on its location.

Autonomic Reflexes

Autonomic reflexes are unconscious motor reflexes relayed from the organs and glands to the CNS through visceral afferent signaling.

The Autonomic Nervous System

The autonomic nervous system (ANS, visceral nervous system, or involuntary nervous system) is the part of the peripheral nervous system that acts as a control system. It functions largely below the level of consciousness and controls visceral functions.

The ANS affects heart rate, digestion, respiratory rate, salivation, perspiration, pupillary dilation, micturition (urination), and sexual arousal. Most autonomic functions are involuntary but a number of ANS actions can work alongside some degree of conscious control. Everyday examples include breathing, swallowing, and sexual arousal, and in some cases functions such as heart rate.

Functions

Within the brain, the ANS is located in the medulla oblongata in the lower brainstem. The medulla’s major ANS functions include respiration (the respiratory control center, or RCC), cardiac regulation (the cardiac control center, or CCC), vasomotor activity (the vasomotor center or VMC), and certain reflex actions (such as coughing, sneezing, vomiting, and swallowing).

These then subdivide into other areas and are also linked to ANS subsystems and nervous systems external to the brain. The hypothalamus, just above the brain stem, acts as an integrator for autonomic functions, receiving ANS regulatory input from the limbic system to do so.

Classifications

The ANS is classically divided into two subsystems: the parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS) that operate independently in some functions and interact co-operatively in others. In many cases, the two have opposite actions. When one activates a physiological response, the other inhibits it.

An older simplification of the sympathetic and parasympathetic nervous systems as excitatory and inhibitory was overturned due to the many exceptions found. A more modern characterization is that the sympathetic nervous system is a quick-response, mobilizing system and the parasympathetic is a more slowly activated, dampening system—but there are exceptions, such as in sexual arousal and orgasm where both play a role.

The enteric nervous system is also sometimes considered part of the autonomic nervous system, and sometimes considered an independent system.

The ANS is unique in that it requires a sequential two-neuron efferent pathway; the preganglionic neuron must first create a synapse to a postganglionic neuron before innervating the target organ. The preganglionic, or first neuron will begin at the outflow and will cross a synapse at the postganglionic, or second neuron’s cell body. The postganglionic neuron will then create a synapse at the target organ.

General visceral afferent sensations are mostly unconscious, visceral motor reflex sensations from hollow organs and glands that are transmitted to the CNS (see the following illustration for a depiction of a typical nerve fiber, including general visceral afferent fibers).

While the unconscious reflex arcs are normally undetectable, in certain instances they may send pain sensations to the CNS, masked as referred pain. If the peritoneal cavity becomes inflamed or if the bowel is suddenly distended, the body will interpret the afferent pain stimulus as somatic in origin. This pain is usually non-localized. The pain is usually referred to as dermatomes that are at the same spinal nerve level as the visceral afferent synapse.

Innervation

Autonomic nerves travel to organs throughout the body. Most organs receive parasympathetic supply by the vagus nerve and sympathetic supply by splanchnic nerves. The sensory part of the latter reaches the spinal column at certain spinal segments. Pain in any internal organ is perceived as referred pain, more specifically as pain from the dermatome corresponding to the spinal segment.^[rx]

Function

Function of the autonomic nervous system ^[rx]

Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is better termed complementary in nature rather than antagonistic. For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic division typically functions in actions requiring quick responses. The parasympathetic division functions with actions that do not require immediate reaction. The sympathetic system is often considered the “fight or flight” system, while the parasympathetic system is often considered the “rest and digest” or “feed and breed” system.

However, many instances of sympathetic and parasympathetic activity cannot be ascribed to “fight” or “rest” situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in blood pressure if not for a compensatory increase in the arterial sympathetic tonus. Another example is the constant, second-to-second, modulation of heart rate by sympathetic and parasympathetic influences, as a function of the respiratory cycles. In general, these two systems should be seen as permanently modulating vital functions, in usually antagonistic fashion, to achieve homeostasis. Higher organisms maintain their integrity via homeostasis which relies on negative feedback regulation which, in turn, typically depends on the autonomic nervous system.^[rx] Some typical actions of the sympathetic and parasympathetic nervous systems are listed below.^[15]

Sympathetic nervous system

Promotes a fight-or-flight response, corresponds with arousal and energy generation, and inhibits digestion

• Diverts blood flow away from the gastrointestinal (GI) tract and skin via vasoconstriction
• Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1200% in the case of skeletal muscles)
• Dilates bronchioles of the lung through circulating epinephrine, which allows for greater alveolar oxygen exchange
• Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for enhanced blood flow to skeletal muscles
• Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and enhances far vision
• Provides vasodilation for the coronary vessels of the heart
• Constricts all the intestinal sphincters and the urinary sphincter
• Inhibits peristalsis
• Stimulates orgasm

Parasympathetic nervous system

The parasympathetic nervous system has been said to promote a “rest and digest” response, promote calming of the nerves return to regular function, and enhancing digestion. Functions of nerves within the parasympathetic nervous system include

• Dilating blood vessels leading to the GI tract, increasing the blood flow.
• Constricting the bronchiolar diameter when the need for oxygen has diminished
• Dedicated cardiac branches of the vagus and thoracic spinal accessory nerves impart parasympathetic control of the heart (myocardium)
• Constriction of the pupil and contraction of the ciliary muscles, facilitating accommodation and allowing for closer vision
• Stimulating salivary gland secretion, and accelerates peristalsis, mediating digestion of food and, indirectly, the absorption of nutrients
• Sexual. Nerves of the peripheral nervous system are involved in the erection of genital tissues via the pelvic splanchnic nerves 2–4. They are also responsible for stimulating sexual arousal.

Enteric nervous system

The enteric nervous system is the intrinsic nervous system of the gastrointestinal system. It has been described as “the Second Brain of the Human Body”.^[rx] Its functions include:

• Sensing chemical and mechanical changes in the gut
• Regulating secretions in the gut
• Controlling peristalsis and some other movements

Neurotransmitters

At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other transmitters such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla:

• Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons. Nerves that release acetylcholine are said to be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter to stimulate muscarinic receptors.
• At the adrenal medulla, there is no postsynaptic neuron. Instead, the presynaptic neuron releases acetylcholine to act on nicotinic receptors. Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream, which acts on adrenoceptors, thereby indirectly mediating or mimicking sympathetic activity.

Comparing the Somatic and Autonomic Nervous Systems

The peripheral nervous system includes both a voluntary, somatic branch and an involuntary branch that regulates visceral functions.

The peripheral nervous system (PNS) is divided into the somatic nervous system and the autonomic nervous system. The somatic nervous system (SoNS) is the part of the peripheral nervous system associated with the voluntary control of body movements via skeletal muscles.

The SoNS consists of efferent nerves responsible for stimulating muscle contraction, including all the non-sensory neurons connected with skeletal muscles and skin. The somatic nervous system controls all voluntary muscular systems within the body, and also mediates involuntary reflex arcs. The somatic nervous system consists of three parts:

1. Spinal nerves are peripheral nerves that carry motor commands and sensory information into the spinal cord.
2. Cranial nerves are the nerve fibers that carry information into and out of the brain stem. They include information related to smell, vision, eyes, eye muscles, the mouth, taste, ears, the neck, shoulders, and the tongue.
3. Association nerves integrate sensory input and motor output; these nerves number in the thousands.

The autonomic nervous system (ANS) is the part of the peripheral nervous system that acts as a control system, functioning largely below the level of consciousness and controlling visceral functions. The ANS affects heart rate, digestion, respiratory rate, salivation, perspiration, pupillary dilation, micturition (urination), and sexual arousal.

Whereas most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind. The ANS is classically divided into two subsystems: the parasympathetic nervous system (PSNS) and the sympathetic nervous system (SNS).

The enteric nervous system is sometimes considered part of the autonomic nervous system and sometimes considered an independent system.

Divisions of the Autonomic Nervous System

The autonomic nervous system (ANS) contains two subdivisions: the parasympathetic (PSNS) and sympathetic (SNS) nervous systems.

The autonomic nervous system (ANS) is classically divided into two subsystems: the parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS). The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes considered an independent system.

Sympathetic and parasympathetic divisions typically function in opposition to each other. This opposition is often viewed as complementary in nature rather than antagonistic. For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake.

The sympathetic division typically functions in actions requiring quick responses. The parasympathetic division functions with actions that do not require immediate reaction. Many think of sympathetic as fight or flight and parasympathetic as rest and digest or feed and breed.

However, many instances of sympathetic and parasympathetic activity cannot be ascribed to fight or rest situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in blood pressure if not for a compensatory increase in the arterial sympathetic tonus.

Another example is the constant, second-to-second modulation of heart rate by sympathetic and parasympathetic influences as a function of the respiratory cycles. More generally, these two systems should be seen as permanently modulating vital functions, in usually antagonistic fashion, to achieve homeostasis.

Some functions of the SNS include diverting blood flow away from the gastrointestinal (GI) tract and skin via vasoconstriction, enhancing blood flow to skeletal muscles and the lungs, dilating the bronchioles of the lung to allow for greater oxygen exchange, and increasing heart rate.

The PSNS typically functions in contrast to the SNS by dilating the blood vessels leading to the GI tract, causing constriction of the pupil and contraction of the ciliary muscle to the lens to enable closer vision, and stimulating salivary gland secretion, in keeping with the rest and digest functions.

Functional Organization of the Vegetative/Autonomic Nervous System

The vegetative or autonomic nervous system (from Greek: autos = self; nomos = law) uses both sensory and efferent neurons, which especially control the function of the internal organs.

The characteristic feature of the autonomic system is that its efferent nerves emerge as medullated fibers from the brain and spinal cord, are interrupted in their course by a synapse in a peripheral ganglion, and are then relayed for distribution as fine, non-medullated fibers. In this respect, they differ from the cerebrospinal efferent nerves, which pass without interruption to their terminations.

The autonomic nervous system allows the higher brain centers (the cerebral cortex and the limbic system) to subconsciously control organs of the autonomic nervous system. It controls functions such as sexual arousal, urination, digestion, and cardiorespiratory functions.

Autonomic nervous system divisions

The autonomic nervous system has 2 divisions based on anatomical, functional, and to a considerable extent, pharmacological grounds: the sympathetic and parasympathetic divisions. The 2 divisions have antagonistic effects on the internal organs they innervate.

Anatomically, the sympathetic nervous system has its motor cell stations in the lateral grey column of the thoracic and upper 2 lumbar segments of the spinal cord. The parasympathetic system is less neatly defined anatomically since it is divided into a cranial outflow, which passes along the cranial nerves 3, 7, 9, and 10, and a sacral outflow, with cell stations in the 2nd, 3rd, and sometimes 4th sacral segments of the cord.

Sensory neurons

The main input of the ANS particularly comes from autonomic sensory (viscerosensory) neurons, which are usually associated with interoceptors and act as sensory receptors in the blood vessels, the visceral organs, and the muscles. These neurons, which have the task to transduce information to the CNS, are usually located in the stomach and the lungs.

Unlike the signals that are triggered by a nice-smelling odor or a delicious-looking meal, the inner sensory signals are normally not experienced consciously, although the activation of the interoceptors can indeed advance into consciousness. Here, 2 typical examples would be the pain caused by damaged intestines or angina pectoris (chest pain) caused by inadequate perfusion of the myocardium.

Efferent neurons

On the other hand, efferent neurons forward the nerve impulses from the CNS to the target tissue (smooth muscle, heart muscle, or glands) and regulate visceral activities by an increase (excitation) or decrease (inhibiting).

Nerves of the sympathetic and parasympathetic nervous systems are responsible for these oppositional effects.

Sympathetic neurons accelerate the heartbeat, support the processes or effort of the body, and enable a ‘fight-or-flight’ reaction. This allows an improvement in performance and consequently, is stimulated in states of excitement, activity, and stress.

Parasympathetic neurons, in contrast, decelerate the heartbeat and induce a ‘rest-and-digest’ reaction. These neurons are responsible for relaxation, recreation, and inducing the regeneration of vital energy reserves.

Efferent responses are not controlled consciously, thus the activity of the ANS is unintentional. So-called ‘lie-detector tests’ are based on several autonomous reactions, since the pulse cannot be manipulated intentionally to half of the standard value. However, some people can alter their autonomic activities by applying adequate relaxing techniques.

Unlike the transmission of the impulse via the somatic motor neurons to the skeletal muscles, transmission to the visceral effectors involves 2 neurons.

Structure of the ANS/VNS

The 1st of the 2 motor neurons in every motoric signaling pathway is called a preganglionic neuron. Its soma is located in the brain or the spinal cord and its axon, on the other hand, leaves the CNS as a part of a cranial nerve or a spinal nerve.

Generally, the preganglionic neuron connects with an autonomic ganglion, where it forms a synapse with the second neuron of the signaling pathway, the postganglionic neuron. The soma and the dendrites of the postganglionic neurons are located in an autonomic ganglion, where they form synapses with 1 or more preganglionic neurons.

The ANS transduces nerve impulses from the preganglionic neurons to the autonomic neurons, where the signals are forwarded to the postganglionic neurons and then transmitted to the target tissue.

The following example deserves mention:

Spinal cord (CNS) → preganglionic neuron → autonomic ganglion → postganglionic neuron → heart (target tissue/effector)

Preganglionic neurons

Thoracolumbar part

The sympathetic part of the ANS is also called the thoracolumbar part since the somas of the preganglionic neurons are located in the lateral horn of the 12 thoracic segments, as well as the 1st 2 or 3 lumbar segments of the spinal cord.

Craniosacral part

On the other hand, the parasympathetic part of the ANS is also referred to as the craniosacral part because the somas of the parasympathetic, preganglionic neurons are located in the nuclei of 4 cranial nerves in the area of the brain stem, as well as in the lateral horns of the second to the fourth sacral segment of the spinal cord.

Autonomic ganglia

Autonomic ganglia are divided into 3 groups:

• Sympathetic chain ganglia
• Sympathetic prevertebral ganglia
• Parasympathetic ganglia

Sympathetic ganglia are located where the synapses between preganglionic and postganglionic sympathetic neurons interact.

Sympathetic chain ganglia

Ganglia of the sympathetic trunk (paravertebral ganglia) are arranged in a vertical column on each side of the spine and reach from the base of the skull down to the coccygeal bone. For the most part, organs above the diaphragm are innervated by the postganglionic axons of the ganglia of the sympathetic trunk.

Sympathetic prevertebral ganglia

Sympathetic prevertebral ganglia are located on the ventral side of the spine close to the large abdominal arteries. On the other hand, postganglionic axons of prevertebral ganglia innervate organs inferior to the diaphragm. The 3 largest prevertebral ganglia are:

• Coeliac ganglion (located right underneath the diaphragm)
• Superior mesenteric ganglion (located in the epigastric region)
• Inferior mesenteric ganglion (located in the umbilical region)

The branches of the sympathetic ganglionic chain have somatic and visceral distribution.

Somatic distribution

Each spinal nerve receives 1 or more grey rami from a sympathetic ganglion which distributes postganglionic non-medullated sympathetic fibers to the segmental skin area supplied by the spinal nerve. These fibers are vasoconstrictive to the skin arterioles, pseudo motor to sweat glands, and pilomotor to the cutaneous hairs.

Visceral distribution

Postganglionic fibers to the head and neck and to the thoracic viscera arise from the ganglion cells of the sympathetic chain. Those to the head ascend along the internal carotid and vertebral arteries, whereas those to the thoracic organs are distributed by the cardiac, pulmonary, and esophageal plexuses.

The abdominal and pelvic viscera are supplied by the postganglionic fibers which have their cell stations in more peripherally-placed prevertebral ganglia—the celiac, hypogastric, and pelvic plexuses—which receive their preganglionic fibers from the splanchnic nerves.

Parasympathetic Ganglia

Preganglionic axons of the parasympathetic nervous system form synapses with postganglionic neurons in terminal or intramural ganglia. For the most part, the ganglia are located near to or inside the wall of an organ.

Axons of preganglionic parasympathetic neurons are usually longer than most of the axons of preganglionic sympathetic neurons since they reach from the CNS all the way to an intramural ganglion of the innervated organ.

Afferent parasympathetic fibers

Visceral afferent fibers from the heart, lungs, and alimentary tract are conveyed in the vagus nerve. Sacral afferents are conveyed in the pelvic splanchnic nerves and are responsible for visceral pain experienced in the bladder, prostate, rectum, and uterus.

Although afferent fibers are conveyed in both sympathetic and parasympathetic nerves, they are completely independent of the autonomic system. They do not relay in the autonomic ganglia and have their cell stations, just like somatic sensory fibers, in the dorsal ganglia of the spinal and cranial nerves. They simply use the autonomic nerves as a convenient anatomical conveyor system from the periphery to the brain.

Postganglionic neurons

Axons of preganglionic sympathetic neurons can be connected to postganglionic neurons by the following 3 possibilities after they have headed to the ganglia of the sympathetic trunk:

1. An axon can form a synapse with a postganglionic neuron directly in the first reached ganglion.
2. An axon can ascend or descend to a higher or lower located ganglion before it is wired up with the postganglionic neuron, which runs vertically next to the sympathetic trunk.
3. An axon can run through the sympathetic ganglion without forming a synapse and end in a prevertebral ganglion to be switched over to the postganglionic neuron.

A single preganglionic sympathetic fiber has many branches, which is the reason why it can be connected with more than 20 or more postganglionic neurons over synapses. The postganglionic axons typically end in different target tissues.

In these ganglia, presynaptic neurons only transmit to 4–5 postsynaptic neurons. They all individually provide a visceral target tissue and, as a consequence, this target tissue can be controlled separately by parasympathetic fibers.

Autonomic plexuses

Axons and sympathetic and parasympathetic neurons form networks that are called autonomic plexuses. They run along large arteries and can be found in the thorax, the abdomen, and the pelvis. The large cardiac plexus in the thorax is in charge of the innervation of the heart and the pulmonary plexus for the bronchial tree.

The largest autonomic plexus is the celiac (solar) plexus, which passes onto the liver, gallbladder, stomach, pancreas, spleen, kidneys, adrenal cortex, testicles, and the ovaries.

Neurotransmitter and Receptors of the ANS/VNS

Neurotransmitters are assigned to receptors – integral membrane proteins that are located in the plasma membrane of the postsynaptic neuron or a cell of the target tissue.

We differentiate between cholinergic and adrenergic neurons.

Cholinergic neurons and receptors

The ANS includes the following cholinergic neurons:

• All sympathetic and parasympathetic preganglionic neurons
• Sympathetic postganglionic neurons for most of the sweat glands
• All postganglionic parasympathetic neurons

Cholinergic neurons release the neurotransmitter acetylcholine (ACh) which is stored in synaptic vesicles and liberated by exocytosis. After that, it diffuses through the synaptic cleft and binds to specific cholinergic receptors.

Cholinergic receptors are further subdivided into the nicotinic and muscarinergic receptors that both bind to ACh.

Nicotinic receptors are embedded in the sympathetic and parasympathetic postganglionic neurons, as well as in the neuromuscular junction. They bear this term because nicotine simulates the action of ACh after binding to the receptors. In non-smokers, this substance is not traceable since nicotine is not a physiologically present substance in the human organism.

However, in the plasma membrane of all target tissues (the smooth muscle, myocardium, and the glands), the muscarinergic receptors are present, which are supplied by the parasympathetic postganglionic axons. An inhibition occurs in several receptors, whereas in others, an excitation occurs. Similarly, sweat glands have muscarinergic receptors which result in increased sweating.

ACh is quickly deactivated by the enzyme acetylcholine esterase and thus, the effects triggered by cholinergic neurons are short.

Adrenergic neurons and receptors

Noradrenaline (NA) is released in the ANS by adrenergic neurons. A great number of postganglionic sympathetic neurons are adrenergic. The NA is stored, just like ACh, in the synaptic vesicles, and released by exocytosis, which diffuses through the synaptic cleft and binds to specific adrenergic receptors of the postsynaptic membrane. The consequence is excitation or inhibition of the effector cell.

NA, as well as adrenaline, binds to the adrenergic receptors. The NA can be released as a neurotransmitter by sympathetic postganglionic neurons or as a hormone by the adrenal medulla, into the blood. Adrenaline is solely released as a hormone.

Also, the adrenergic receptors can again be subdivided into 2 subtypes which are innervated by most of the postganglionic sympathetic neurons. They are called alpha (α)-receptors and beta (β)-receptors, which are further subdivided according to their specific answers and the corresponding binding properties (α1, α2, β1, β2, etc.).

Broadly speaking, an activation of the α1- and β1-receptors induces an excitation, whereas α2- and β2-receptors yield an inhibition of the target tissue.

Autonomic reflexes

Answers that are triggered by the nerve impulses in an autonomic reflex arc are called autonomic reflexes. They play a key role in the following processes:

• Blood pressure (i.e. by adjusting the heart rate)
• Digestion (adjustment of motility and muscle tone in the GI tract)
• Defecation
• Urination (regulating the opening and closing of the sphincter)

The main control and integration center of the ANS is the hypothalamus, which receives sensory information about visceral functions (smell, taste, temperature etc.). Signals of the limbic system, which cohere with emotions, influence this process as well. The signals coming from the hypothalamus affect the autonomous centers in the brain stem, as well as in the spinal cord (medulla spinalis).

An autonomic reflex arc consists of the following components:

Receptor

• The distal end of a sensory neuron is the receptor of an autonomic reflex arc, which reacts to a stimulus and triggers a nerve impulse. Usually, autonomic sensory receptors are associated with interoceptors.

Sensory neurons

• The sensory neuron forwards nerve impulses to the CNS.

Integration center

• The main integration centers for the autonomic reflexes are located in the hypothalamus and the brain stem. Some autonomic reflexes are situated in the integration centers of the spinal cord, which are mostly responsible for urination and defecation.
• Connectivity: interneurons of the CNS forward signals from the sensory neurons to the motor neurons.

Motor neurons

• Signals triggered by the integration centers leave the CNS, via motor neurons, towards the target tissue. Two motor neurons connect the CNS in an autonomic reflex arc with the effector. The impulse is transduced by the preganglionic neuron to an autonomic ganglion from where it is forwarded through the postganglionic neuron to the target tissue.

Target tissue (effector)

• The effectors of the autonomic reflex are the smooth muscles, the heart muscle, or the glands.

Clinical Significance

Due to the extensive nature of the autonomic nervous system, it can be affected by a wide range of conditions. Some of these include[rx][rx][rx]

• Diabetes mellitus
• Uremic neuropathy/chronic liver diseases
• Vitamin B12 deficiency
• Toxin/drug-induced: alcohol, amiodarone, chemotherapy
• Infections: Botulism, Chagas disease, HIV, leprosy, Lyme disease, tetanus
• Autoimmune: Guillain-Barre, Lambert-Eaton myasthenic syndrome, rheumatoid arthritis, Sjogren, systemic lupus erythematosus
• Neurological: multiple system atrophy/Shy-Drager syndrome, Parkinson disease, Lewy body dementia/
  Neoplasia: Brain tumors, paraneoplastic syndromes

Likewise, autonomic neuropathy can present in nearly any system. Orthostatic hypotension is the most common autonomic dysautonomia, but numerous other, less understood, findings may present[rx]

• Fixed heart rate
• Postural hypotension
• Resting tachycardia

• Dysphagia
• Gastroparesis; nausea, vomiting, abdominal fullness
• Constipation

• Bladder atony

• Absent/delayed light reflexes
• Decreased pupil size

• Erectile dysfunction
• Retrograde ejaculation

• Anhidrosis
• Gustatory sweating

• Cold extremities (due to loss of vasomotor responses)
• Edema (due to loss of vasomotor tone and increased vascular permeability)

The most prevalent symptoms of orthostatic hypotension are lightheadedness, tunnel vision, and discomfort in the head, neck, or chest. It may present concomitantly with supine hypertension due to increased peripheral resistance, which induces natriuresis, exacerbating orthostatic hypotension. There are numerous other, more benign stimuli that may either lower blood pressure (standing, food, Valsalva, dehydration, exercise, hyperventilation, etc.) or raise blood pressure (lying supine, water ingestion, coffee, head-down tilt, hypoventilation, etc.).[rx]

References

Sound

Sound waves, characterized by frequency and amplitude, are perceived uniquely by different organisms.

Sound

Auditory stimuli are sound waves, which are mechanical pressure waves that move through a medium, such as air or water. There are no sound waves in a vacuum since there are no air molecules for the waves to move through. The speed of sound waves differs based on altitude, temperature, and medium. At sea level and a temperature of 20º C (68º F), sound waves travel in the air at about 343 meters per second.

As is true for all waves, there are four main characteristics of a sound wave: frequency, wavelength, period, and amplitude. Frequency is the number of waves per unit of time; in sound, it is heard as pitch. High-frequency (≥15.000Hz) sounds are higher-pitched (short wavelength) than low-frequency (long wavelengths; ≤100Hz) sounds. Frequency is measured in cycles per second. For sound, the most commonly used unit is hertz (Hz), or cycles per second. Most humans can perceive sounds with frequencies between 30 and 20,000 Hz. Women are typically better at hearing high frequencies, but everyone’s ability to hear high frequencies decreases with age. Dogs detect up to about 40,000 Hz; cats, 60,000 Hz; bats, 100,000 Hz; dolphins, 150,000 Hz; and the American shad (Alosa sapidissima), a fish, can hear 180,000 Hz. Those frequencies above the human range are called ultrasound.

The amplitude or the dimension of a wave from peak to trough, in sound is heard as volume. The sound waves of louder sounds have greater amplitude than those of softer sounds. For sound, volume is measured in decibels (dB). The softest sound that a human can hear is the zero point. Humans speak normally at 60 decibels.

The Vestibular System

Gravity, acceleration, and deceleration are detected by evaluating the inertia on receptive cells in the vestibular system.

Vestibular Information

The stimuli associated with the vestibular system are linear acceleration (gravity) and angular acceleration/deceleration. Gravity, acceleration, and deceleration are detected by evaluating the inertia on receptive cells in the vestibular system. Gravity is detected through head position, while angular acceleration and deceleration are expressed through turning or tilting of the head.

The vestibular system has some similarities with the auditory system. It utilizes hair cells just like the auditory system, but it excites them in different ways. There are five vestibular receptor organs in the inner ear, all of which help to maintain balance: the utricle, the saccule, and three semicircular canals. Together, they make up what is known as the vestibular labyrinth. The utricle and saccule are most responsive to acceleration in a straight line, such as gravity. The roughly 30,000 hair cells in the utricle and 16,000 hair cells in the saccule lie below a gelatinous layer, with their stereocilia (singular: stereocilium) projecting into the gelatin. Embedded in this gelatin are calcium carbonate crystals, similar to tiny rocks. When the head is tilted, the crystals continue to be pulled straight down by gravity, but the new angle of the head causes the gelatin to shift, thereby bending the stereocilia. The bending of the stereocilia stimulates specific neurons that signal to the brain that the head is tilted, allowing the maintenance of balance. It is the vestibular branch of the vestibulocochlear cranial nerve that deals with balance.

 

Vestibular labyrinth: The structure of the vestibular labyrinth is made up of five vestibular receptor organs in the inner ear: the utricle, the saccule, and three semicircular canals.

The fluid-filled semicircular canals are tubular loops set at oblique angles, arranged in three spatial planes. The base of each canal has a swelling that contains a cluster of hair cells. The hairs project into a gelatinous cap, the cupula, where they monitor angular acceleration and deceleration from rotation. They would be stimulated by driving your car around a corner, turning your head, or falling forward. One canal lies horizontally, while the other two lie at about 45-degree angles to the horizontal axis. When the brain processes input from all three canals together, it can detect angular acceleration or deceleration in three dimensions. When the head turns, the fluid in the canals shifts, thereby bending stereocilia and sending signals to the brain. Upon cessation of acceleration or deceleration, the movement of the fluid within the canals slows or stops. For example, imagine holding a glass of water. When moving forward, water may splash backward onto the hand; when motion has stopped, water may splash forward onto the fingers. While in motion, the water settles in the glass and does not splash. Note that the canals are not sensitive to velocity itself but to changes in velocity. In this way, moving forward at 60 mph with your eyes closed would not give the sensation of movement, but suddenly accelerating or braking would stimulate the receptors.

Higher Processing

Hair cells from the utricle, saccule, and semicircular canals also communicate through bipolar neurons to the cochlear nucleus in the medulla. Cochlear neurons send descending projections to the spinal cord and ascending projections to the pons, thalamus, and cerebellum. Connections to the cerebellum are important for coordinated movements. There are also projections to the temporal cortex, which accounts for feelings of dizziness; projections to autonomic nervous system areas in the brainstem, which account for motion sickness; and projections to the primary somatosensory cortex, which monitors subjective measurements of the external world and self-movement. People with lesions in the vestibular area of the somatosensory cortex see vertical objects in the world as being tilted. Finally, the vestibular signals project to certain optic muscles to coordinate eye and head movements.

Reception of Sound

The outer, middle, and inner structures of the ear collect sound energy, converting it to audible sound.

Reception of Sound

In order to hear a sound, the auditory system must accomplish three basic tasks. First, it must deliver the acoustic stimulus to the receptors; second, it must convert the stimulus from pressure changes into electrical signals; and third, it must process these electrical signals so that they can efficiently indicate the qualities of the sound source, such as frequency (pitch), amplitude (loudness, volume), and location.

The human ear can be divided into three functional segments:

• the outer ear: collects sound energy from the environment and sends it to the eardrum
• the middle ear: transduces the mechanical pressure signals from the ear drum into electrical signals
• the inner ear: interprets the electrical signals from the middle ear using hair cells

In mammals, sound waves are collected by the external, cartilaginous outer part of the ear called the pinna. They then travel through the auditory canal, causing vibration of the thin diaphragm called the tympanum, or ear drum, the innermost part of the outer ear. Interior to the tympanum is the middle ear, which holds three small bones called the ossicles (“little bones”), that transfer energy from the moving tympanum to the inner ear. The three ossicles are the malleus (also known as the hammer), the incus (the anvil), and stapes (the stirrup). The three ossicles are unique to mammals; each plays a role in hearing. The malleus attaches at three points to the interior surface of the tympanic membrane. The incus attaches the malleus to the stapes. In humans, the stapes is not long enough to reach the tympanum. If we did not have the malleus and the incus, then the vibrations of the tympanum would never reach the inner ear. These bones also function to collect force and amplify sounds. The ear ossicles are homologous to bones in a fish mouth; the bones that support gills in fish are thought to be adapted for use in the vertebrate ear over evolutionary time. Many animals (frogs, reptiles, and birds, for example) use the stapes of the middle ear to transmit vibrations to it.

 

Human ear: Sound travels through the outer ear to the middle ear, which is bounded on its exterior by the tympanic membrane. The middle ear contains three bones called ossicles that transfer the sound wave to the oval window, the exterior boundary of the inner ear.

Transduction of Sound

When sound waves reach the ear, the ear transduces this mechanical stimulus (pressure) into a nerve impulse (electrical signal) that the brain perceives as sound.

Vibrating objects, such as vocal cords, create sound waves or pressure waves in the air. When these pressure waves reach the ear, the ear transduces this mechanical stimulus (pressure wave) into a nerve impulse (electrical signal) that the brain perceives as sound. The pressure waves strike the tympanum, causing it to vibrate. The mechanical energy from the moving tympanum transmits the vibrations to the three bones of the middle ear. The stapes transmits the vibrations to a thin diaphragm called the oval window, which is the outermost structure of the inner ear.

 

Diagram of the middle ear: The middle ear exists between the tympanic membrane (the boundary with the outer ear) and the oval window (the boundary with the inner ear) and consists of three bones: the malleus (meaning hammer), the incus (meaning anvil), and the stapes (meaning stirrup).

The structures of the inner ear are found in the labyrinth, a bony, hollow structure that is the most interior portion of the ear. Here, the energy from the sound wave is transferred from the stapes through the flexible oval window and to the fluid of the cochlea. The vibrations of the oval window create pressure waves in the fluid (perilymph) inside the cochlea. The cochlea is a whorled structure, like the shell of a snail, and it contains receptors for the transduction of the mechanical wave into an electrical signal. Inside the cochlea, the basilar membrane is a mechanical analyzer that runs the length of the cochlea, curling toward the cochlea’s center.

 

Inner ear: The inner ear can be divided into three parts: the semicircular canals, the vestibule, and the cochlea, all of which are located in the temporal bone.

The mechanical properties of the basilar membrane change along its length, such that it is thicker, tauter, and narrower at the outside of the whorl (where the cochlea is largest), and thinner, floppier, and broader toward the apex, or center, of the whorl (where the cochlea is smallest). Different regions of the basilar membrane vibrate according to the frequency of the sound wave conducted through the fluid in the cochlea. For these reasons, the fluid-filled cochlea detects different wave frequencies (pitches) at different regions of the membrane. When the sound waves in the cochlear fluid contact the basilar membrane, it flexes back and forth in a wave-like fashion. Above the basilar membrane is the tectorial membrane.

 

Transduction: In the human ear, sound waves cause the stapes to press against the oval window. Vibrations travel up the fluid-filled interior of the cochlea. The basilar membrane that lines the cochlea gets continuously thinner toward the apex of the cochlea. Different thicknesses of membrane vibrate in response to different frequencies of sound. Sound waves then exit through the round window. In the cross-section of the cochlea (top right figure), note that in addition to the upper canal and lower canal, the cochlea also has a middle canal. The organ of the Corti (bottom image) is the site of sound transduction. The movement of stereocilia on hair cells results in an action potential that travels along the auditory nerve.

The site of transduction is in the organ of Corti (spiral organ). It is composed of hair cells held in place above the basilar membrane like flowers projecting up from the soil, with their exposed short, hair-like stereocilia contacting or embedded in the tectorial membrane above them. The inner hair cells are the primary auditory receptors and exist in a single row, numbering approximately 3,500. The stereocilia from inner hair cells extend into small dimples on the tectorial membrane’s lower surface. The outer hair cells are arranged in three or four rows. They number approximately 12,000, and they function to fine-tune incoming sound waves. The longer stereocilia that project from the outer hair cells actually attach to the tectorial membrane. All of the stereocilia are mechanoreceptors, and when bent by vibrations they respond by opening a gated ion channel (refer to [link]). As a result, the hair cell membrane is depolarized, and a signal is transmitted to the cochlear nerve. The intensity (volume) of sound is determined by how many hair cells at a particular location are stimulated.

The hair cells are arranged on the basilar membrane in an orderly way. The basilar membrane vibrates in different regions, according to the frequency of the sound waves impinging on it. Likewise, the hair cells that lay above it are most sensitive to a specific frequency of sound waves. Hair cells can respond to a small range of similar frequencies, but they require stimulation of greater intensity to fire at frequencies outside of their optimal range. The difference in response frequency between adjacent inner hair cells is about 0.2 percent. Compare that to adjacent piano strings, which are about six percent different. Place theory, which is the model for how biologists think pitch detection works in the human ear, states that high-frequency sounds selectively vibrate the basilar membrane of the inner ear near the entrance port (the oval window). Lower frequencies travel farther along the membrane before causing appreciable excitation of the membrane. The basic pitch-determining mechanism is based on the location along the membrane where the hair cells are stimulated. The place theory is the first step toward an understanding of pitch perception. Considering the extreme pitch sensitivity of the human ear, it is thought that there must be some auditory “sharpening” mechanism to enhance the pitch resolution.

When sound waves produce fluid waves inside the cochlea, the basilar membrane flexes, bending the stereocilia that attach to the tectorial membrane. Their bending results in action potentials in the hair cells, and auditory information travels along the neural endings of the bipolar neurons of the hair cells (collectively, the auditory nerve) to the brain. When the hairs bend, they release an excitatory neurotransmitter at a synapse with a sensory neuron, which then conducts action potentials to the central nervous system. The cochlear branch of the vestibulocochlear cranial nerve sends information on hearing. The auditory system is very refined, and there is some modulation or “sharpening” built in. The brain can send signals back to the cochlea, resulting in a change of length in the outer hair cells, sharpening or dampening the hair cells’ response to certain frequencies.

Higher Processing

The inner hair cells are most important for conveying auditory information to the brain. About 90 percent of the afferent neurons carry information from inner hair cells, with each hair cell synapsing with 10 or so neurons. Outer hair cells connect to only 10 percent of the afferent neurons, and each afferent neuron innervates many hair cells. The afferent, bipolar neurons that convey auditory information travel from the cochlea to the medulla, through the pons and midbrain in the brainstem, finally reaching the primary auditory cortex in the temporal lobe.

References

Pain Sensation

Pain is an unpleasant sensation caused by the activation of nociceptors by thermal, mechanical, chemical, or other stimuli.

Overview

Pain is an unpleasant feeling often caused by intense or damaging stimuli, such as stubbing a toe, burning a finger, putting alcohol on a cut, and bumping the funny bone. The International Association for the Study of Pain’s widely used definition states: “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

Pain motivates the individual to withdraw from damaging situations, to protect a damaged body part while it heals, and to avoid similar experiences in the future. Most pain resolves promptly once the painful stimulus is removed and the body has healed, but sometimes pain persists despite removal of the stimulus and apparent healing of the body. Pain sometimes arises in the absence of any detectable stimulus, damage, or disease.

Nociceptors

A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain. There are several types and functions of nociceptors:

• Thermal nociceptors are activated by noxious heat or cold at various temperatures.
• Mechanical nociceptors respond to excess pressure or mechanical deformation. They also respond to incisions that break the skin surface. These mechanical nociceptors frequently have polymodal characteristics. So it is possible that some of the transducers for thermal stimuli are the same for mechanical stimuli.
• Chemical nociceptors respond to a wide variety of spices commonly used in cooking. The one that sees the most response and is very widely tested is capsaicin. Other chemical stimulants are environmental irritants like acrolein, a World War I chemical weapon and a component of cigarette smoke. Besides these external stimulants, chemical nociceptors have the capacity to detect endogenous ligands, and certain fatty acid amines that arise from changes in internal tissues.

The peripheral terminal of the mature nociceptor is where the noxious stimuli are detected and transduced into electrical energy. When the electrical energy reaches a threshold value, an action potential is induced and driven towards the central nervous system. This leads to the train of events that allows for the conscious awareness of pain.

 

Gray matter in the spinal cord: A delta fibers (Aδ fibers), a type of sensory fiber, are associated with the sensation of cold and pressure. Aδ fibers are thinly myelinated; therefore, they conduct signals more rapidly than unmyelinated C fibers, but more slowly than other, more thickly myelinated “A” class fibers. Aδ fibers terminate at Rexed laminae I and V (labeled I and V in the diagram). C fibers respond to thermal, mechanical, and chemical stimuli and terminate at the Rexed lamina II (labeled II in the diagram).

Nociceptors have two different types of axons.

1. The Aδ fiber axons are myelinated and can allow an action potential to travel at a rate of about 20 meters/second towards the central nervous system.
2. The other type is the more slowly conducting C fiber axons. These only conduct at speeds of around 2 meters/second. This is due to the light or nonmyelination of the axon.

Phases of Pain

Pain comes in two phases. The first phase is mediated by the fast-conducting Aδ fibers, and the second part is due to C fibers. The pain associated with the Aδ fibers can be associated to an initial extremely sharp pain.

The second phase is a more prolonged and slightly less intense feeling of pain as a result of the damage. If there is massive or prolonged input to a C fiber, there is a progressive build up in the spinal cord dorsal horn; this phenomenon is similar to tetanus in muscles but is called wind-up. If wind-up occurs, there is a probability of increased sensitivity to pain.

Although each nociceptor can have a variety of possible threshold levels, some do not respond at all to chemical, thermal, or mechanical stimuli unless injury actually has occurred. These are typically referred to as silent or sleeping nociceptors since their response comes only at the onset of inflammation to the surrounding tissue.

Types of Nociceptive Pain

Nociceptive pain can be divided into visceral, deep somatic, and superficial somatic pain.

• Visceral structures are highly sensitive to stretch, ischemia, and inflammation, but relatively insensitive to other stimuli that normally evoke pain in other structures, such as burning and cutting. Visceral pain is diffuse, difficult to locate, and often referred to as a distant, usually superficial, structure. It may be accompanied by nausea and vomiting and may be described as sickening, deep, squeezing, and dull.
• Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae, and muscles, and is a dull, aching, poorly localized pain. Examples include sprains and broken bones.
• Superficial pain is initiated by the activation of nociceptors in the skin or other superficial tissue and is sharp, well-defined, and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first-degree) burns.

Localization of Pain

Localization of pain is determined by whether the pain is superficial somatic, visceral, or deep somatic.

Pain Categories

Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors) and maybe classified according to the mode of noxious stimulation.

The most common categories are thermal (heat or cold), mechanical (crushing, tearing, etc.), and chemical (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into visceral, deep somatic, and superficial somatic pain.

Visceral Pain

Visceral structures are highly sensitive to stretch, ischemia, and inflammation, but relatively insensitive to other stimuli that normally evoke pain in other structures, such as burning and cutting. Visceral pain is diffuse, difficult to locate, and often referred to a distant, usually superficial, structure. It may be accompanied by nausea and vomiting and may be described as sickening, deep, squeezing, and dull.

Deep Somatic Pain

Deep somatic pain is initiated by the stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae, and muscles, and is a dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or other superficial tissue, and is sharp, well-defined, and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns.

Referred Pain

Referred pain (also reflective pain) is pain perceived at a location other than the site of the painful stimulus. An example is the case of ischemia brought on by a myocardial infarction ( heart attack), where pain is often felt in the neck, shoulders, and back rather than in the chest, the site of the injury.

The International Association for the Study of Pain has not officially defined referred pain as of 2001; hence, several authors have defined the term differently. Radiation is different from referred pain.

The pain related to a myocardial infarction could either be referred pain or pain radiating from the chest. Classically, the pain associated with a myocardial infarction is located in the middle or left side of the chest, where the heart is actually located. The pain can radiate to the left side of the jaw and into the left arm.

Referred pain occurs when the pain is located away from or adjacent to the organ involved. An example would be when a person has pain only in their jaw or left arm, but not in the chest. The size of referred pain is related to the intensity and duration of ongoing/evoked pain.

Also, temporal summation is a potent mechanism for the generation of referred muscle pain. Central hyperexcitability is also important for the extent of referred pain.

 

Temporal summation: Temporal summation, shown in the diagram, is the transmitting of signals with increased frequency of impulse, thus increasing the strength of signals in each fiber. Temporal summation is a potent mechanism for the generation of referred muscle pain.

 

Brain freeze: In an ice cream headache, known colloquially as brain freeze and medically as a cold-stimulus headache, the trigeminal nerve, shown in yellow, conducts signals from dilating blood vessels in the palate to the brain that interpret the pain as coming from the forehead.

References

Show More

• https://www.ncbi.nlm.nih.gov/books/NBK539789/
• https://www.ncbi.nlm.nih.gov/books/NBK338120/
• https://www.ncbi.nlm.nih.gov/books/NBK219252/
• https://www.ncbi.nlm.nih.gov/books/NBK556098/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939729/
• https://www.ncbi.nlm.nih.gov/books/NBK470523/

Components of a Reflex Arc

A reflex arc defines the pathway by which a reflex travels—from the stimulus to sensory neuron to motor neuron to reflex muscle movement.

Description

A reflex action, also known as a reflex, is an involuntary and nearly instantaneous movement in response to a stimulus. When a person accidentally touches a hot object, they automatically jerk their hand away without thinking. A reflex does not require any thought input.

The path taken by the nerve impulses in a reflex is called a reflex arc. In higher animals, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord. This characteristic allows reflex actions to occur relatively quickly by activating spinal motor neurons without the delay of routing signals through the brain, although the brain will receive sensory input while the reflex action occurs.

Most reflex arcs involve only three neurons. The stimulus, such as a needle stick, stimulates the pain receptors of the skin, which initiate an impulse in a sensory neuron. This travels to the spinal cord where it passes, by means of a synapse, to a connecting neuron called the relay neuron situated in the spinal cord.

The relay neuron in turn makes a synapse with one or more motor neurons that transmit the impulse to the muscles of the limb causing them to contract and pull away from the sharp object. Reflexes do not require involvement of the brain, although in some cases the brain can prevent reflex action.

 

Reflex arc: The path taken by the nerve impulses in a reflex is called a reflex arc. This is shown here in response to a pin in the paw of an animal, but it is equally adaptable to any situation and animal (including humans).

Types of Reflex Arcs

There are two types of reflex arcs = the autonomic reflex arc, which affecting inner organs, and the somatic reflex arc, affecting muscles. When a reflex arc consists of only two neurons, one sensory neuron, and one motor neuron, it is defined as monosynaptic.

Monosynaptic refers to the presence of a single chemical synapse. In the case of peripheral muscle reflexes (patellar reflex, Achilles reflex), brief stimulation to the muscle spindle results in the contraction of the agonist or effector’s muscle.

By contrast, in polysynaptic reflex arcs, one or more interneurons connect afferent (sensory) and efferent (motor) signals.
For example, the withdrawal reflex (nociceptive or flexor withdrawal reflex) is a spinal reflex intended to protect the body from damaging stimuli. It causes the stimulation of sensory, association, and motor neurons.

Spinal Reflexes

Spinal reflexes include the stretch reflex, the Golgi tendon reflex, the crossed extensor reflex, and the withdrawal reflex.

Spinal reflexes include the stretch reflex, the Golgi tendon reflex, the crossed extensor reflex, and the withdrawal reflex.

Stretch Reflex

The stretch reflex (myotatic reflex) is a muscle contraction in response to stretching within the muscle. This reflex has the shortest latency of all spinal reflexes. It is a monosynaptic reflex that provides automatic regulation of skeletal muscle length.

When a muscle lengthens, the muscle spindle is stretched and its nerve activity increases. This increases alpha motor neuron activity, causing the muscle fibers to contract and thus resist the stretching. A secondary set of neurons also causes the opposing muscle to relax. The reflex functions to maintain the muscle at a constant length.

Golgi Tendon Reflex

The Golgi tendon reflex is a normal component of the reflex arc of the peripheral nervous system. The tendon reflex operates as a feedback mechanism to control muscle tension by causing muscle relaxation before muscle force becomes so great that tendons might be torn.

Although the tendon reflex is less sensitive than the stretch reflex, it can override the stretch reflex when tension is great, making you drop a very heavyweight, for example. Like the stretch reflex, the tendon reflex is ipsilateral.

The sensory receptors for this reflex are called Golgi tendon receptors and lie within a tendon near its junction with a muscle. In contrast to muscle spindles, which are sensitive to changes in muscle length, tendon organs detect and respond to changes in muscle tension that are caused by a passive stretch or muscular contraction.

Crossed Extensor Reflex

Jendrassik maneuver

The Jendrassik maneuver is a medical maneuver wherein the patient flexes both sets of fingers into a hook-like form and interlocks those sets of fingers together (note the hands of the patient in the chair). This maneuver is used often when testing the patellar reflex, as it forces the patient to concentrate on the interlocking of the fingers and prevents conscious inhibition or influence of the reflex.

The crossed extensor reflex is a withdrawal reflex. The reflex occurs when the flexors in the withdrawing limb contract and the extensors relax, while in the other limb, the opposite occurs. An example of this is when a person steps on a nail, the leg that is stepping on the nail pulls away, while the other leg takes the weight of the whole body.

The crossed extensor reflex is contralateral, meaning the reflex occurs on the opposite side of the body from the stimulus. To produce this reflex, branches of the afferent nerve fibers cross from the stimulated side of the body to the contralateral side of the spinal cord. There, they synapse with interneurons, which in turn, excite or inhibit alpha motor neurons to the muscles of the contralateral limb.

Withdrawal Reflex

The withdrawal reflex (nociceptive or flexor withdrawal reflex) is a spinal reflex intended to protect the body from damaging stimuli. It is polysynaptic and causes the stimulation of sensory, association, and motor neurons.

When a person touches a hot object and withdraws his hand from it without thinking about it, the heat stimulates temperature and danger receptors in the skin, triggering a sensory impulse that travels to the central nervous system. The sensory neuron then synapses with interneurons that connect to motor neurons. Some of these sends motor impulses to the flexors to allow withdrawal.

Some motor neurons send inhibitory impulses to the extensors so flexion is not inhibited—this is referred to as reciprocal innervation. Although this is a reflex, there are two interesting aspects to it:

1. The body can be trained to override that reflex.
2. An unconscious body (or even drunk or drugged bodies) will not exhibit the reflex.

References