INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Robert A. Nichols, Ph.D. Reading: Objectives: 1. To understand the anatomical and functional differences of the two divisions of the ANS 2. To understand the neurotransmitter chemistry of the ANS 3. To compare the physiology and pharmacology of the ANS 4. To discuss the autonomic control of individual organs General Considerations: The activities of the ANS occur in the absence of any direct conscious control (=involuntary). Anatomically, the ANS has two major divisions: the Parasympathetic nervous system and the Sympathetic nervous system. (The Enteric nervous system, which receives parasympathetic and sympathetic input, has been sometimes referred to as a third division, owing the interconnectivity and autonomy of most of its neural circuitry.) Though the activities in both divisions are subject to higher-level integration in the brain, they behave in distinctly different manners, often, but not always, mutually antagonistic. Key Issues: The parasympathetic nervous system acts to facilitate the normal functioning of the organs, and each individual parasympathetic pathway is regulated independently. The sympathetic nervous system often (but not always) acts to help an organism respond to various kinds of stress (eg. “flight” or “fright”), and, as a whole, can be and often is activated in a concerted manner. Basic Microanatomy of the ANS: 1. All preganglionic cell bodies reside in nuclei in the CNS, giving rise to preganglionic nerves that exit the CNS and innervate cells in distinct ganglia. 2. The ganglionic cell body (sometimes called the postganglionic cell, unfortunately) gives rise to a postganglionic nerve that then innervates a particular target tissue/organ. 3. The synaptic contact between postganglionic nerve and the tissue/organ is oft referred to as the neuroeffector junction. Rang et al., Pharmacology, Chapter 9
Anatomy of the two major divisions: (see Fig. 9.1 in Rang et al.) A. Parasympathetic nervous system 1. Preganglionic nerves arise from three brain regions: midbrain, medulla and sacral spinal cord. The midbrain fibers follow cranial nerve III (oculomotor); the medullary fibers follow cranial nerves VII (facial), IX (glossopharyngeal), and X (vagus); the sacral fibers arise from cells in the 2nd, 3rd and 4th segments of the sacral spinal cord. 2. Preganglionic parasympathetic nerves are very long and are myelinated, innervating ganglia that often reside at, or even in the target organ. The postganglionic nerves are thus typically short and are unmyelinated. 3. Usually (except the vagus) the ratio of preganglionic to postganglionic fibers is one-to-one. B. Sympathetic nervous system 1. Preganglionic nerves arises from middle segments of the spinal cord: thoracic and lumbar 2. Each preganglionic cell gives rise to multiple fibers that innervate cells in the either the paravertebral sympathetic chain (mainly), the prevertebral ganglia (celiac and mesenteric) or the (very few) terminal ganglia in the target organs. 3. Most preganglionic sympathetic nerves are short and are myelinated, whereas the postganglionic nerves are long and are unmyelinated. 4. Adrenal medullary chromaffin cells are essentially sympathetic ganglion cells and are innervated by typical preganglionic sympathetic nerve fibers. Neurochemistry of the ANS: ALL preganglionic fibers release acetylcholine (=cholinergic) Postganglionic PARASYMPATHETIC fibers release acetylcholine(=cholinergic) Postganglionic SYMPATHETIC fibers release norepinephrine(=adrenergic) Exceptions: i. Adrenal medullary chromaffin cells secrete epinephrine ii. Sympathetic nerves innervating sweat glands secrete acetylcholine iii. Sympathetic nerves innervating blood vessels in skeletal muscle secrete acetylcholine iv. Sympathetic nerves innervating renal blood vessels secrete dopamine
Receptors in the ANS and its targets: 1. All preganglionic fibers release acetylcholine onto Nicotinic acetylcholine receptors on the ganglionic cell bodies. [Muscarinic acetylcholine receptors are also present, but are not primarily involved in basic synaptic neurotransmission in the ANS] Postganglionic parasympathetic fibers release acetylcholine onto M2 or M3 Muscarinic acetylcholine receptors residing in the target organs. Postganglionic sympathetic fibers release norepinephrine onto Alpha-1, Beta-1 or Beta-2 Adrenergic receptors residing in particular target organs. Norepinephrine released from postganglionic sympathetic fibers can act on Alpha-2 Adrenergic receptors residing on the same sympathetic nerve endings (=autoregulatory).
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Receptors and Responses in Individual Organs/Tissues: I. Eye - parasympathetic: cholinergic innervation of sphincter muscles via M3 receptors causes contraction and miosis (=constriction of the pupil) - sympathetic: adrenergic innervation of the radial muscles via Alpha1 receptors causes contraction and mydriasis (=dilation of the pupil) - both innervate the ciliary musculature in the anterior chamber: contraction (via M3) of the ciliary muscle allows accommodation of focus for near vision and (important) opens the Canal of Schlemm, allowing outflow of aqueous humor. [Beta receptors in the ciliary epithelium facilitate secretion of aqueous humor and blocking them sharply reducing formation of humor, lowering intraocular pressure.]
II. Lungs (Bronchi) - parasympathetic: cholinergic fibers via M3 receptors cause muscles to contract, reducing the airway - sympathetic: sparse adrenergic innervation via Beta2 receptors cause bronchial muscles to relax, opening the airway (little role in humans; major role in dogs); receptors are probably more in tune with circulating epinephrine than with norepinephrine secreted from sympathetic nerves
III. Heart parasympathetic: cholinergic fibers via M2 receptors decrease heart rate (=bradycardia) largely by acting on the sinoatrial node. [Only small effect on force of contraction] - sympathetic: adrenergic fibers via Beta1 receptors increase heart rate (=tachycardia) at the sinoatrial node and the force of contraction (positive ionotropy) in the ventricles
IV. Blood Vessels (Vasculature) - parasympathetic: NO innervation of blood vessels by parasympathetic fibers [exception: small action on coronary arteries - don’t worry about it]. Note, however, that muscarinic receptors are present on the vessel endothelium (not the muscle) and, when activated, cause release of nitric oxide (EDRF), which, in turn, induces relaxation and hence dilitation of the vessels carotid baroreceptors: changes in mean arterial pressure are sensed by specialized structures in the carotid sinus, the baroreceptors, and signal the vasomotor center via
sensory parasympathetic fibers. The baroreceptor response, also sometimes referred to as the vagal reflex, operates as a negative feedback loop, wherein a rise in blood pressure induces a strong increase in parasympathetic discharge in the heart (vagus), with a concomitant decrease in sympathetic outflow, reducing the overall cardiac output, and vice versa for a drop in pressure.
sympathetic: adrenergic fibers via Alpha1 receptors contract and hence constrict (resistance) blood vessels, raising blood pressure. Beta2 receptors are also present and respond to circulating epinephrine by dilating vessels, lowering blood pressure. D1 dopamine receptors and H1 histamine receptors are present in many vascular beds and, when activated, cause enough dilation to lower blood pressure. [Many resistance vessels contain Alpha2 receptors in their walls, ie. extrasynaptic, which, when activated, also cause constriction; however, long-term treatment with Alpha2 agonist will lead to relaxation due to action on presynaptic sympathetic fibers to reduce secretion of norepinephrine] Exceptions: adrenergic fibers via D1 dopamine receptors relax and hence dilate renal blood vessels; cholinergic sympathetic fibers innervate vessels in skeletal muscle via muscarinic receptors, causing dilatation (with little effect on blood pressure)
V. Gastrointestinal Tract - parasympathetic: stimulation of M3 receptors leads to an increase in peristalsis (contraction) and relaxation of sphincter - sympathetic: stimulation of Beta2 decreases peristalsis (relaxation) and of Alpha1/ Alpha2 receptors constricts the sphincter
VI. Bladder - parasympathetic: cholinergic innervation via M3 causes contraction of the bladder wall and relaxation of the sphincter - sympathetic: adrenergic fibers via Beta2 cause relaxation of the bladder wall and via Alpha1/ Alpha2 cause contraction of the sphincter [Autonomic control overlays the basic spinal reflex for micturition, which is primarily triggered by bladder distension] VII. Salivary/Lacrimal Glands - both induce secretion from the salivary glands: largely parasympathetic innervation via M3 induces normal, watery saliva; activation of sympathetic innervation via Alpha1 induces secretion of thick saliva; - lacrimation is largely parasympathetic
VIII. Liver - parasympathetic: NONE - sympathetic: stimulation via (=glycogen breakdown) IX. Skin
Beta2 receptors increases glycogenolysis
A. Sweat glands - parasympathetic: NONE - sympathetic: cholinergic innervation via muscarinic receptors induces generalized sweating. [Localized sweating, eg. palms, occurs via adrenergic receptors] B. Pilomotor muscles - parasympathetic: NONE - sympathetic: adrenergic innervation via Alpha1 receptors induces piloerection of hair follicles
X. Fat Cells (sympathetic) adrenergic stimulation via (=thermogenic)
Beta3 receptors induces lipolysis
XI. Adrenal Gland - preganglionic sympathetic fibers act via nicotinic acetylcholine receptors to release epinephrine from adrenal chromaffin cells (~ganglion-like cells). The level of circulating catecholamine is a very, very important contributor to blood pressure control.
XII. Kidney - Beta1 receptors mediate the release of renin - D1 Dopamine receptors mediate renal vascular dilation