Which neurotransmitter is released from the parasympathetic ganglion?
Introduction to the Autonomic Nervous System (ANS)By the end of this session you should be able to: Show
Abbreviations & Definitions:
Part I: IntroductionThe autonomic nervous system (ANS) or involuntary nervous system acts as a control system, coordinating bodily functions to maintain homeostasis (Hamill et al, 2012). The ANS affects:
Many of the functions of the ANS, such as regulating breathing, heart rate, blood pressure and cardiovascular reflexes are controlled by respiratory, vasomotor & cardiac control centers in the medulla oblongata (lower brain stem). The ANS is classically divided into two major subsystems, the parasympathetic nervous system and the sympathetic nervous system (Figure 1). In some cases the two systems operate independently (e.g. regulation of arterial tone by the sympathetic nervous system), while in others they operate cooperatively (e.g. regulation of heart rate) (Figure 1 & Table 1). In “most” organ systems, the parasympathetic nervous system displays a “predominant tone”, meaning it has a stronger influence on tissue function when the body is at rest, as compared to the sympathetic nervous system (Table 2). Three major exceptions include the vasculature, sweat glands, and the ventricular myocardium, where the sympathetic nervous system exerts a dominant influence when the body is at rest, due to a lack of parasympathetic innervation (Table 1).
 Figure 1. Schematic of the autonomic nervous system and major organs that they effect. The neurotransmitter released by most postganglionic sympathetic nerves is norepinephrine (NorEpi), which stimulates postsynaptic α & β receptors on target organs. The expression of different α & β receptors and their subtypes (e.g. α1,α2,β1,β2,β3) is tissue specific. One exception to the rule are sweat glands, which are innervated by postganglionic sympathetic nerves that release acetylcholine (ACh). ACh is also the major neurotransmitter released by postganglionic nerves in the parasympathetic nervous system, as well as preganglionic nerves in both the sympathetic and parasympathetic nervous system. Nicotinic receptors (N) mediate neurotransmission in the ganglia of both sympathetic and parasympathetic nervous systems. They have a different subunit composition & pharmacology compared to nicotinic receptors expressed in skeletal muscle and in the CNS. Where Did the All These Terms ("Sympathetic", "Nicotinic", "Muscarinic"...) Come From?The origin of the term “sympathetic” as applied to the nervous system is attributed to Galen (AD 130-200), one of the greatest anatomists and physiologists of ancient Rome. Galen anatomically described the ganglionated (sympathetic) chain that ran alongside the spinal cord and innervated various internal organs. Galen postulated that these nerves were involved in sensory functions, and were hollow, which allowed “animal spirits” to go from one organ to another, producing the phenomenon of physiological “sympathy” between internal organs (Ackerknect, 1974; Finger 1994). “Epinephrine” was a new term proposed in the late 1800's by John Abel (one of the founding fathers of modern pharmacology) who used it to label the active ingredient obtained from extracts of the adrenal glands. The origin of the word relates to the anatomical location of the adrenal glands above the kidney (“epi-” means “above”, and “nephros” being the Greek word for kidney). In 1901 Jokichi Takamine, a Japanese chemist working in a small independent laboratory in New York City (supported by Parke, Davis) purified the active ingredient from the adrenal gland and called it “adrenaline” (Wikipedia). In the United States adrenaline was later given the generic name “epinephrine” (Wikipedia). Adrenaline (epinephrine) was first effective bronchodilator for asthma, and the first glandular hormone ever purified. The neurotransmitter released by sympathetic nerves was later determined to be a naturally occurring demethylated analog of epinephrine, which was given the name norepinephrine (Goodman & Gilman, 1956). The term “parasympathetic” originated in the early 20th century. Para means “alongside”, and many of the nerves in this group of cholinergic nerves run alongside sympathetic nerves ( Oxford dictionary). Many of the other terms used to describe autonomic responses were derived from terms used by the original scientific pioneers including Paul Ehrlich (1854–1915) and John Newport Langley (1852-1925) who postulated that drugs and hormones work by interacting with specific “receptors”, and elucidated the actions of acetylcholine, norepinephrine and epinephrine (Maehle, 2004). In 1933 Sir Henry Dale (1936 Nobel laureate) proposed the used of “cholinergic” and “adrenergic” to refer to nerves fibers and their stimulatory effects without reference to their anatomical origin (1936 Nobel lecture). Langley used nicotine in his investigations of autonomic anatomy because of its recognized ability to transiently stimulate and then block all nervous conduction in autonomic ganglia. Nicotine was later shown to produce similar effects at skeletal neuromuscular junctions. Therefore, cholinomimetic agents that had a selective effect at ganglia or the neuromuscular junction were termed “nicotinic”. In contrast to nicotine, the poisonous mushroom alkaloid muscarine, and its antagonist atropine appeared to exert their effects on the peripheral endings of the parasympathetic nervous system (such as the vagal fibers leading to the heart). At one point it was postulated that the vagus might liberate a muscarine-like substance from its nerve endings on the heart. Therefore, the adjective “muscarinic” is employed to characterize the actions of acetylcholine at postganglionic parasympathetic neuroeffector junctions, or by any cholinomimetic agent whose effects are largely limited to these junctions.
Figure 2. Comparison of nicotinic and muscarinic receptors. Different subtypes of ligand gated receptors for acetylcholine that are associated with ion channels are expressed in skeletal muscle and ganglia, as well as some locations in the CNS. Binding of acetylcholine (ACh) to these receptors opens an ion channel that is nonselective for sodium and potassium. Opening of these channels evokes membrane depolarization. The subunit composition of nicotinic receptor-channel complexes differs in ganglia, skeletal muscle, and within the CNS, resulting in differences in sensitivity to different agonists and antagonists. In contrast to nicotinic receptors, the cholinergic binding sites that are selective for muscarine are G-protein coupled receptors found in a variety of tissues including glands (sweat and salavary), heart and smooth muscle, vascular endothelial cells, and multiple areas within the CNS including those involved with cognition and memory. Five different muscarinic receptors have been cloned, and different G proteins (such as Gi, & Gq) can mediate signal transduction depending upon both the muscarinic receptor subtype and tissue involved. The actions of acetylcholine on both nicotinic and muscarinic are rapidly terminated by acetylcholinesterase (AChE), which is expressed at high levels by tissues expressing these receptors. AChE rapidly hydrolyses acetylcholine to acetic acid and choline, which are biologically inactive, and which are subsequently taken up by presynaptic nerves in order to re-synthesize acetylcholine within the nerve terminal. Reversible inhibitors of AChE (cholinesterase inhibitors, or “anti-cholinesterases”) such as neostigmine will cause a build up of acetylcholine, resulting in increased stimulation of both muscarinic and nicotinic receptors. In contrast, organophosphate type cholinesterase inhibitors bind irreversibly to AChE, and can cause extremely intense and prolonged stimulation of both muscarinic and nicotinic sites, which can be life threatening (e.g. as observed after exposure to the chemical warfare agents agents such ase sarin or soman). Anatomy of the ANSAnatomically, neurons in the sympathetic nervous system originate in the thoracic & lumbar region of the spinal cord (T1-L2/3), and neurons in the parasympathetic nervous system originate from either cranial or sacral regions of the spinal cord (Figure 1). Both branches of the ANS have a 2 neuron efferent pathway involving a preganglionic nerve that synapses with a postganglionic nerve before innervating the target organ (with the exception of the adrenal gland). The neurotranmitter in the ganglia of both parasympathetic and sympathetic nervous systems is acetylcholine, which activates a unique “nicotinic ganglionic” receptor on the postganglionic membrane that has a different subunit composition compared to nicotinic receptors expressed in the neuromuscular junction. The different subunit composition results in a different sensitivity to drugs. For example skeletal muscle nicotinic receptors can be selectively antagonized by analogs of the South American arrow poison tubocurarine (an alkaloid found in the bark of a South American climbing vine). The ability of tubocurarine to rapidly produce severe skeletal muscle relaxation (including paralysis of the diaphragm) made it a useful weapon for hunting wild game when using a bow & arrow. Tubocurarine analogs are now commonly used as adjunct drugs to prevent spontaneous muscle movements, or to facilitate intubation during major surgical procedures. In contrast the ganglionic nicotinic receptor subtype can be selectively antagonized by synthetic several synthetic drugs (e.g. hexamethonium, mecamylamine & trimethaphan) that were originally developed as 1st generation antihypertensive agents (Figure 3). Administration of a ganglionic blocker will reduce or eliminate the effects produced by predominant tone, as well as any baroreceptor-mediated reflex changes that normally regulate heart rate and blood pressure (Table 2). Administration of drugs that selectively antagonize nicotinic receptors expressed by skeletal muscle will produce a flaccid muscle paralysis that is useful during major surgical procedures (or when hunting deer in a rain forest).
Figure 3. Schematic of different branches of the peripheral nervous system (e.g. parasympathetic, sympathetic and motor nervous systems)(the sensory nervous system is not shown). The ganglia for both the parasympathetic and sympathetic nervous systems utilize the same NG subtype of nicotinic cholinergic receptors for synaptic communication. The NG ganglionic nicotinic receptors have a different subunit composition compared to those nicotinic receptors expressed by skeletal muscle (NM). Mecamylamine and trimethaphan are “ganglionic blockers” which selective block NG receptors. Tubocurarine and succinylcholine are prototype selective antagonists of the skeletal muscle NM receptor subtype. Parasympathetic Nervous SystemAcetylcholine is the major neurotransmitter released by postganglionic parasympathetic neurons. The release of acetylcholine stimulates muscarinic (M1-M5) receptors expressed on target organs (Figures 1,2 &3). The parasympathetic branch of the ANS is not arranged for massive discharge, and instead is designed for control of individual organs. Parasympathetic ganglia tend to be close to, or within the organ innervated, with most organ systems having a 1:1 ratio of preganglionic to postganglionic fibers, providing a discrete and local discharge that is useful for conservation of energy and maintenance of organ function during periods of minimal activity (“rest and digest”). No useful purpose would be achieved if this division were to be discharged all at one time. In fact, massive parasympathetic discharge, as occurs with poisoning by organophosphate nerve agents (e.g. sarin) can result in a life-threatening “SLUDE” syndrome, which is an acronym for “Salivation”, “Lacrimation”, “Urination”, “Defecation” and “Emesis”. Sympathetic Nervous SystemNorepinephrine is the major neurotransmitter released by postganglionic sympathetic neurons (Figure 1). One exception to the general rule in the sympathetic nervous system is the adrenal medulla, which is directly innervated by a preganglionic sympathetic neurons that release acetylcholine which acts on nicotinic receptors of the adrenal gland to stimulate the release of epinephrine (adrenaline) into the bloodstream, along with a small amount of norepinephrine. Sympathetic nerves can be called upon to discharge in unison (in contrast to the parasympathetic nervous system). This results in the release of both norepinephrine from nerve terminals, and epinephrine from the adrenal gland, producing a series of “fight or flight” responses that include increased:
Part II: Muscarinic & Nicotinic EffectsA knowledge of the effects of parasympathetic vs sympathetic stimulation on major effector organs, as well as which branch exerts a predominant tone, allows one to predict the actions of drugs that mimic or inhibit the actions of these nerves. Tables 1 & 2 provide a summary of the effects of sympathetic (adrenergic) and parasympathetic (cholinergic) stimulation and predominant tone, and what effect results when predominant tone is lost.
NOTE: β2 responses are mediated by circulating epinephrine; β2 receptors are typically not located near sympathetic nerve endings. Adapted from Westfall et al (2018) and Katzung (2021) Part III: Predominant Tone
EpilogueDon't forget to review the related module on Autonomic Dysfunction Pathophysiology which highlights the importance of understanding the concepts of predominant tone and baroreceptor mediated reflexes involved in maintaining heart rate and blood pressure. You have to have a working knowledge and understanding of the role of the receptors and neural pathways of the ANS before you can understand the basis for the signs and symptoms observed in patients with different forms of autonomic dysfunction, one of which (POTS) affects over 500,000 patients living in the United States! References
Which neurotransmitter is released at the ganglion?Both sympathetic and parasympathetic preganglionic neurons are cholinergic, meaning they release acetylcholine (Ach) at the synapse in the ganglion.
Which neurotransmitters are used with the sympathetic and parasympathetic nervous system?Both the sympathetic and parasympathetic nerves release neurotransmitters, primarily norepinephrine and epinephrine for the sympathetic nervous system, and acetylcholine for the parasympathetic nervous system.
What is released by parasympathetic nerves?Parasympathetic nerves traveling within the vagus nerve release acetylcholine to act upon M2 and M3 muscarinic receptors on airway smooth muscle. The nerve terminals also express autoinhibitory M2 muscarinic receptors that respond to released acetylcholine to inhibit further neurotransmitter release.
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