Neurotransmission: Autonomic and Somatic Nervous Systems PDF

Section II Neuropharmacology Chapter 10. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems / 173 Chapter 11. Muscarinic Receptor Agonists and Antagonists / 207 Chapter 12. Anticholinesterase Inhibitors and Reactivators / 221 Chapter 13. Neuromuscular Junction...

Section II Neuropharmacology Chapter 10. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems / 173 Chapter 11. Muscarinic Receptor Agonists and Antagonists / 207 Chapter 12. Anticholinesterase Inhibitors and Reactivators / 221 Chapter 13. Neuromuscular Junction and Autonomic Ganglia; Nicotine, Muscle Relaxants, and Spasmolytics / 235 Chapter 14. Adrenergic Agonists and Antagonists / 251 Chapter 15. 5-Hydroxytryptamine (Serotonin) and Dopamine / 285 Chapter 16. Neurotransmission in the Central Nervous System / 305 Chapter 17. The Blood-Brain Barrier and Its Influence on Drug Transport to the Brain / 327 Chapter 18. Drug Therapy of Depression and Anxiety Disorders / 343 Chapter 19. Pharmacotherapy of Psychosis and Mania / 357 Chapter 20. Pharmacotherapy of the Epilepsies / 385 Chapter 21. Treatment of Central Nervous System Degenerative Disorders / 413 Chapter 22. Hypnotics and Sedatives / 427 Chapter 23. Opioid Analgesics / 443 Chapter 24. General Anesthetics and Therapeutic Gases / 471 Chapter 25. Local Anesthetics / 489 Chapter 26. Cannabinoids / 505 Chapter 27. Ethanol / 519 Chapter 28. Drug Use Disorders and Addiction / 531 https://ebooksmedicine.net/ This page intentionally left blank  10Chapter ANATOMY AND GENERAL FUNCTIONS Neurotransmission: The Autonomic and Somatic Motor Nervous Systems Rebecca Petre Sullivan, Steven R. Houser, and Walter J. Koch Differences Between Autonomic and Somatic Nerves Divisions of the Peripheral Autonomic System PHARMACOLOGICAL CONSIDERATIONS Interference With the Synthesis or Release of the Transmitter Promotion of Release of the Transmitter Comparison of Sympathetic, Parasympathetic, and Motor Nerves Agonist and Antagonist Actions at Receptors Interference With the Destruction of the Transmitter NEUROCHEMICAL TRANSMISSION Evidence for Neurohumoral Transmission OTHER AUTONOMIC NEUROTRANSMITTERS Steps Involved in Neurotransmission Cotransmission in the Autonomic Nervous System Cholinergic Transmission Nonadrenergic, Noncholinergic Transmission by Purines Adrenergic Transmission Signal Integration and Modulation of Vascular Responses by Endothelium-Derived Factors: NO and Endothelin Cranial visceral sensory information enters the CNS by four cranial Anatomy and General Functions nerves: the trigeminal (V), facial (VII), glossopharyngeal (IX), and vagus The autonomic nervous system, also called the visceral, vegetative, or (X) nerves. These four cranial nerves transmit visceral sensory informa- involuntary nervous system, is distributed widely throughout the body tion from the internal face and head (V); tongue (taste, VII); hard palate and regulates autonomic functions that occur without conscious control. and upper part of the oropharynx (IX); and carotid body, lower part of In the periphery, it consists of nerves, ganglia, and plexuses that innervate the oropharynx, larynx, trachea, esophagus, and thoracic and abdominal the heart, blood vessels, glands, other visceral organs, and smooth muscle organs (X), with the exception of the pelvic viscera. The pelvic viscera in various tissues. This system enables the body to constantly monitor, are innervated by nerves from the second through fourth sacral spinal analyze, and anticipate needs, and control the response to the organ sys- segments. The visceral afferents from these four cranial nerves terminate tems, in order to maintain homeostasis. topographically in the solitary tract nucleus (STN). Sensory afferents from visceral organs also enter the CNS from the Differences Between Autonomic spinal nerves. Those concerned with muscle chemosensation may arise and Somatic Nerves at all spinal levels, whereas sympathetic visceral sensory afferents gener- ally arise at the thoracic levels where sympathetic preganglionic neurons The efferent nerves of the autonomic nervous system supply all inner- are found. Pelvic sensory afferents from spinal segments S2–S4 enter at vated structures of the body except skeletal muscles, which are served that level and are important for the regulation of sacral parasympathetic by somatic nerves. outflow. In general, visceral afferents that enter the spinal nerves convey The most distal synaptic junctions in the autonomic reflex arc occur in information concerned with temperature as well as nociceptive visceral ganglia that are entirely outside the cerebrospinal axis. Somatic nerves inputs related to mechanical, chemical, and thermal stimulation. The pri- contain no peripheral ganglia, and the synapses are located entirely mary pathways taken by ascending spinal visceral afferents are complex. within the cerebrospinal axis. An important feature of the ascending pathways is that they provide col- Many autonomic nerves form extensive peripheral plexuses; such net- laterals that converge with the cranial visceral sensory pathway at virtu- works are absent from the somatic system. ally every level (Saper, 2002). Postganglionic autonomic nerves generally are nonmyelinated; motor The neurotransmitters that mediate transmission from sensory fibers nerves to skeletal muscles are myelinated. have not been characterized unequivocally. Substance P and calcitonin When the spinal efferent nerves are interrupted, smooth muscles and gene-related peptide (CGRP), present in afferent sensory fibers, dorsal glands generally retain some level of spontaneous activity, whereas the root ganglia, and the dorsal horn of the spinal cord, likely communicate denervated skeletal muscles are paralyzed. nociceptive stimuli from the periphery to the spinal cord and higher structures. Somatostatin (SST), vasoactive intestinal polypeptide (VIP), Sensory Information: Afferent Fibers and Reflex Arcs and cholecystokinin also occur in sensory neurons (Hökfelt et al., 2000). Afferent fibers from visceral structures are the first link in the reflex arcs ATP appears to be a neurotransmitter in certain sensory neurons (e.g., the of the autonomic system. With certain exceptions, such as local axon urinary bladder). Enkephalins, present in interneurons in the dorsal spinal reflexes, most visceral reflexes are mediated through the CNS. cord (within the substantia gelatinosa), have antinociceptive effects both Visceral Afferent Fibers. Information on the status of the visceral pre- and postsynaptically to inhibit the release of substance P and dimin- organs is transmitted to the CNS through two main sensory systems: ish the activity of cells that project from the spinal cord to higher centers the cranial nerve (parasympathetic) visceral sensory system and the spi- in the CNS. The excitatory amino acids glutamate and aspartate also play nal (sympathetic) visceral afferent system. The cranial visceral sensory major roles in transmission of sensory responses to the spinal cord. These system carries mainly mechanoreceptor and chemosensory information, transmitters and their signaling pathways are reviewed in Chapter 16. whereas the afferents of the spinal visceral system principally convey sen- Central Autonomic Connections sations related to temperature and tissue injury of mechanical, chemical, There probably are no purely autonomic or somatic centers of integration, https://ebooksmedicine.net/ or thermal origin. and extensive overlap occurs. Somatic responses always are accompanied  174 Abbreviations nervous system exist above the level of the spinal cord. For example, integration of the control of respiration in the medulla oblongata is well known. The hypothalamus and the STN generally are regarded as prin- ACh: acetylcholine cipal loci of integration of autonomic nervous system functions, which AChE: acetylcholinesterase include regulation of body temperature, water balance, carbohydrate and BuChE: butyrylcholinesterase fat metabolism, blood pressure, emotions, sleep, respiration, and repro- CaM: calmodulin duction. Signals are received through ascending spinobulbar pathways, CGRP: calcitonin gene-related peptide the limbic system, neostriatum, cortex, and to a lesser extent other higher CHT1: choline transporter brain centers. Stimulation of the STN and the hypothalamus activates COMT: catechol-O-methyltransferase bulbospinal pathways, which originate in the brainstem, and hormonal output to mediate autonomic and motor responses (Andresen and Kunze, DA: dopamine 1994) (see Chapter 16). The hypothalamic nuclei that lie posteriorly and DAT: DA transporter laterally are sympathetic in their main connections and are responsible CHAPTER 10 NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS DβH: dopamine β-hydroxylase for myriad responses including body temperature regulation, blood pres- DOMA: 3,4-dihydroxymandelic acid sure, and pupillary dilation (posterior hypothalamus), and cardiovascular DOPEG: 3,4-dihydroxyphenyl glycol control, feeding, satiety, and insulin release (lateral hypothalamus). Para- DOPGAL: dihydroxyphenylglycolaldehyde sympathetic functions evidently are integrated by the midline nuclei in ENS: enteric nervous system the region of the tuber cinereum and by nuclei lying anteriorly. ENT: extraneuronal transporter Highly integrated patterns of response generally are organized at a EPI: epinephrine hypothalamic level and involve autonomic, endocrine, and behavioral EPSP: excitatory postsynaptic potential components. More limited patterned responses are organized at other ICC: interstitial cells of Cajal levels of basal forebrain, brainstem, and spinal cord. GABA: γ-aminobutyric acid GI: gastrointestinal Divisions of the Peripheral Autonomic System GPCR: G protein-coupled receptor On the efferent side, the autonomic nervous system consists of two large 5HT: serotonin (5-hydroxytryptamine) divisions: (1) the sympathetic or thoracolumbar outflow, which includes ICC: interstitial cells of Cajal T1–L2, and (2) the parasympathetic or craniosacral outflow, which IP3: inositol 1,4,5-trisphosphate includes cranial nerves III, VII, IX, and X, as well as S2–S4. Figure 10–1 IPSP: inhibitory postsynaptic potential schematically summarizes the arrangement of the principal parts of the KO: knockout peripheral autonomic nervous system. mAChR: muscarinic acetylcholine receptor MAO: monoamine oxidase Neurotransmitters of the Autonomic Nervous System MAPK: mitogen-activated protein kinase The neurotransmitter of all preganglionic autonomic fibers, most post- MOPEG: 3-methyl,4-hydroxyphenylglycol ganglionic parasympathetic fibers, and a few postganglionic sympathetic MOPGAL: monohydroxyphenylglycolaldehyde fibers is acetylcholine (Ach). Some postganglionic parasympathetic nAChR: nicotinic ACh receptor nerves use nitric oxide (NO) as a neurotransmitter and are termed NE: norepinephrine (noradrenaline) nitrergic (Toda and Okamura, 2003). The majority of the postganglionic NET: norepinephrine transporter sympathetic fibers are adrenergic, in which the transmitter is norepi- NMJ: neuromuscular junction (of skeletal muscle) nephrine (NE; also called noradrenaline). The terms cholinergic NO: nitric oxide and adrenergic describe neurons that liberate ACh or NE, respectively. NOS: nitric oxide synthase Not all the transmitters of the primary afferent fibers, such as those from NPY: neuropeptide Y the mechano- and chemoreceptors of the carotid body and aortic arch, NSF: N-ethylmaleamide sensitive factor have been identified conclusively. Substance P and glutamate may medi- PACAP: pituitary adenylyl cyclase–activating peptide ate many afferent impulses; both are present in high concentrations in the PK_: protein kinase _, as in PKA dorsal horn of the spinal cord. PL_: phospholipase _, as in PLA2, PLC, etc. PNMT: phenylethanolamine-N-methyltransferase Sympathetic Nervous System The cells that give rise to the preganglionic fibers of the sympathetic SA: sinoatrial nervous system division lie mainly in the intermediolateral columns of SLC: solute carrier the spinal cord and extend from the first thoracic to the second or third SNAP: soluble NSF attachment protein, synaptosome-associated lumbar segment. The axons from these cells are carried in the anterior protein (ventral) nerve roots and synapse, with neurons lying in sympathetic gan- SNARE: SNAP receptor glia outside the cerebrospinal axis. Sympathetic ganglia are found in three SST: somatostatin locations: paravertebral, prevertebral, and terminal. STN: solitary tract nucleus The 22 pairs of paravertebral sympathetic ganglia form the lateral TH: tyrosine hydroxylase chains on either side of the vertebral column. The ganglia are connected VIP: vasoactive intestinal polypeptide to each other by nerve trunks and to the spinal nerves by rami commu- VMA: vanillyl mandelic acid nicantes. The white rami are restricted to the segments of the thoracol- VMAT2: vesicular uptake transporter umbar outflow; they carry the preganglionic myelinated fibers that exit the spinal cord by the anterior spinal roots. The gray rami arise from the ganglia and carry postganglionic fibers back to the spinal nerves for by visceral responses and vice versa. Autonomic reflexes can be elicited distribution to sweat glands and pilomotor muscles and to blood vessels at the level of the spinal cord. They clearly are demonstrable in exper- of skeletal muscle and skin. The prevertebral ganglia lie in the abdomen imental animals or humans with spinal cord transection and are man- and the pelvis near the ventral surface of the bony vertebral column and ifested by sweating, blood pressure alterations, vasomotor responses to consist mainly of the celiac (solar), superior mesenteric, aorticorenal, and temperature changes, and reflex emptying of the urinary bladder, rectum, inferior mesenteric ganglia. The terminal ganglia are few in number, lie and seminal vesicles. Extensive central ramifications of the autonomic near the organs they innervate, and include ganglia connected with the  175 ciliary ganglion iris ciliary body tectobulbar (cranial) outflow cervical cord lacrimal gland III mechano- and chemoreceptors sphenopalatine ganglion internal carotid of carotid carotid sinus sinus and carotid carotid body body chorda tympani sublingual gland VII otic submaxillary gland IX parotid gland ganglion X arch of aorta vasosensitive and SECTION II superior superior chemoreceptive endings middle cervical ganglia cervical ganglia heart inferior 1 trachea NEUROPHARMACOLOGY stellate ganglion bronchi lungs 2 pulmonary vessels 3 paravertebral ganglionic liver 4 chain bile ducts gall bladder gallbladder t 5 oo alr thoracic cord rs paravertebral ganglionic chain celiac ganglion 6 thoracicolumbar outflow do spleen al stomach greater ventr small bowel splanchnic 7 proximal colon les ast s 8 paravertebral le ser pla adrenal ganglion spl nch medulla 9 white ramus an nic gray ramus chn 10 kidney ic ureter 11 skeletal muscle 12 distal superior colon mesenteric 1 lumbar cord ganglion 2 blood vessels rectum 3 pelvic nerve urinary 4 bladder 5 external 1 genitalia sacral outflow 2 sacral ganglia inferior 3 mesenteric 4 ganglion 5 To blood vessels To sweat glands and and hair follicles specialized blood vessels of lower limb of lower limb Segmental postganglionic Segmental postganglionic adrenergic fibers from cholinergic fibers from paravertebral ganglia to paravertebral ganglia to blood vessels and hair sweat glands and certain follicles via gray rami blood vessels via gray and spinal nerves rami and spinal nerves Figure 10–1 The autonomic nervous system. Schematic representation of the autonomic nerves and effector organs based on chemical mediation of nerve impulses. Yellow ( ), cholinergic; red ( ), adrenergic; dotted blue ( ), visceral afferent; solid lines, preganglionic; broken lines, postganglionic. The rectangle at right shows the finer details of the ramifications of adrenergic fibers at any one segment of the spinal cord, the path of the visceral afferent nerves, the cholinergic nature of somatic motor nerves to skeletal muscle, and the presumed cholinergic nature of the vasodilator fibers in the dorsal roots of the spinal https://ebooksmedicine.net/ nerves. The asterisk (*) indicates that it is not known whether these vasodilator fibers are motor or sensory or where their cell bodies are situated.  176 urinary bladder and rectum and the cervical ganglia in the region of the Enteric Nervous System neck. In addition, small intermediate ganglia lie outside the conventional The processes of mixing, propulsion, and absorption of nutrients in the vertebral chain, especially in the thoracolumbar region. They are variable gastrointestinal (GI) tract are controlled locally through a restricted part in number and location but usually are in proximity to the communicat- of the peripheral nervous system called the enteric nervous system (ENS). ing rami and the anterior spinal nerve roots. The ENS comprises components of the sympathetic and parasympathetic Preganglionic fibers issuing from the spinal cord may synapse with the nervous systems and has sensory nerve connections through the spinal neurons of more than one sympathetic ganglion. Their principal ganglia and nodose ganglia (see Figure 54–1 and Furness et al., 2014). The ENS is of termination need not correspond to the original level from which the involved in sensorimotor control and thus consists of both afferent sen- preganglionic fiber exits the spinal cord. Many of the preganglionic fibers sory neurons and a number of motor nerves and interneurons that are from the fifth to the last thoracic segment pass through the paraverte- organized principally into two nerve plexuses: the myenteric (Auerbach) bral ganglia to form the splanchnic nerves. Most of the splanchnic nerve plexus and the submucosal (Meissner) plexus. The myenteric plexus, fibers do not synapse until they reach the celiac ganglion; others directly located between the longitudinal and circular muscle layers, plays an innervate the adrenal medulla. important role in the contraction and relaxation of GI smooth muscle, CHAPTER 10 NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS Postganglionic fibers arising from sympathetic ganglia innervate therefore exerting control over peristaltic movements and gastrointestinal visceral structures of the thorax, abdomen, head, and neck. The trunk motility. The submucosal plexus is involved with secretory and absorp- and the limbs are supplied by the sympathetic fibers in spinal nerves. tive functions of the GI epithelium, local blood flow, and neuroimmune The prevertebral ganglia contain cell bodies whose axons innervate the activities. The microbiota of the gut, the immune system, and their inter- glands and smooth muscles of the abdominal and the pelvic viscera. actions with the ENS inform GI homeostasis and may play a role in the Many of the upper thoracic sympathetic fibers from the vertebral ganglia development of neurodegenerative diseases (Obata and Pachnis, 2016). form terminal plexuses, such as the cardiac, esophageal, and pulmonary Parasympathetic preganglionic inputs are provided to the GI tract via plexuses. The sympathetic distribution to the head and the neck (vaso- the vagus and pelvic nerves. ACh released from preganglionic neurons motor, pupillodilator, secretory, and pilomotor) is by means of the cer- activates nicotinic ACh receptors (nAChRs) on postganglionic neurons vical sympathetic chain and its three ganglia. All postganglionic fibers within the enteric ganglia. Excitatory preganglionic input activates both in this chain arise from cell bodies located in these three ganglia. All excitatory and inhibitory motor neurons that control processes such as preganglionic fibers arise from the upper thoracic segments of the spinal muscle contraction and secretion/absorption. Postganglionic sympathetic cord, there being no sympathetic fibers that leave the CNS above the first nerves also synapse with intrinsic neurons and generally induce relaxation. thoracic level. Sympathetic input is excitatory (contractile) at some sphincters. Informa- Pharmacologically, anatomically, and embryologically, the chromaffin tion from afferent and preganglionic neural inputs to the enteric ganglia cells of the adrenal medulla resemble a collection of postganglionic sym- is integrated and distributed by a network of interneurons. ACh is the pri- pathetic nerve cells. Typical preganglionic fibers that release ACh inner- mary neurotransmitter providing excitatory inputs between interneurons, vates these chromaffin cells, stimulating the release of epinephrine (EPI; but other substances, such as ATP (via postjunctional P2X receptors), sub- also called adrenaline), in distinction to the NE released by postgangli- stance P (by NK3 receptors), and serotonin (5HT; via 5HT3 receptors), are onic sympathetic fibers. also important in mediating integrative processing via interneurons. The muscle layers of the GI tract are dually innervated by excitatory Parasympathetic Nervous System and inhibitory motor neurons, with cell bodies primarily in the myenteric The parasympathetic nervous system consists of preganglionic fibers ganglia. ACh is a primary excitatory motor neurotransmitter released from that originate in the CNS and their postganglionic connections. The postganglionic neurons. ACh activates M2 and M3 receptors in postjunc- regions of central origin are the midbrain, the medulla oblongata, and the tional cells to elicit motor responses. Pharmacological blockade of mus- sacral part of the spinal cord. The midbrain, or tectal, outflow consists of carinic acetylcholine receptors (mAChRs) does not block all excitatory fibers arising from the Edinger-Westphal nucleus (accessory oculomotor neurotransmission, however, because neurokinins (neurokinin A and nucleus) of the third cranial nerve and going to the ciliary ganglion in substance P) are also co-released by excitatory motor neurons and contrib- the orbit. The medullary outflow consists of the parasympathetic compo- ute to postjunctional excitation. Inhibitory motor neurons in the GI tract nents of cranial nerves VII, IX, and X. regulate motility events such as accommodation, sphincter relaxation, and The fibers in the VII (facial) cranial nerve form the chorda tympani, descending receptive relaxation. Inhibitory responses are elicited by NO and which innervates the ganglia lying on the submaxillary and sublingual a purine derivative (either ATP or β-nicotinamide adenine dinucleotide) glands. They also form the greater superficial petrosal nerve, which acting at postjunctional P2Y1 receptors. Inhibitory neuropeptides, such as innervates the sphenopalatine ganglion. The autonomic components VIP and pituitary adenylyl cyclase–activating peptide, may also be released of the IX (glossopharyngeal) cranial nerve innervate the otic ganglia. from inhibitory motor neurons under conditions of strong stimulation. Postganglionic parasympathetic fibers from these ganglia supply the In general, motor neurons do not directly innervate smooth muscle sphincter of the iris (pupillary constrictor muscle), the ciliary muscle, cells in the GI tract. Nerve terminals make synaptic connections with the salivary and lacrimal glands, and the mucous glands of the nose, the interstitial cells of Cajal (ICCs), and these cells make electrical con- mouth, and pharynx. These fibers also include vasodilator nerves to nections (gap junctions) with smooth muscle cells. Thus, the ICCs are these same organs. Cranial nerve X (vagus) arises in the medulla and the receptive, postjunctional transducers of inputs from enteric motor contains preganglionic fibers, most of which do not synapse until they neurons, and loss of these cells has been associated with conditions that reach the many small ganglia lying directly on or in the viscera of the appear to be neuropathies. ICCs have all of the major receptors and effec- thorax and abdomen. In the intestinal wall, the vagal fibers terminate tors necessary to transduce both excitatory and inhibitory neurotrans- around ganglion cells in the myenteric and submucosal plexuses. Thus, mitters into postjunctional responses (Foong et al., 2020). in the parasympathetic branch of the autonomic nervous system, pregan- glionic fibers are very long, whereas postganglionic fibers are very short. Comparison of Sympathetic, Parasympathetic, The vagus nerve also carries a far greater number of afferent fibers from and Motor Nerves the viscera into the medulla. The parasympathetic sacral outflow con- Differences among somatic motor, sympathetic, and parasympathetic sists of axons that arise from cells in the second, third, and fourth seg- nerves are shown schematically in Figure 10–2. To summarize: ments of the sacral cord and proceed as preganglionic fibers to form the pelvic nerves (nervi erigentes). They synapse in terminal ganglia lying The sympathetic system is distributed to effectors throughout the body, near or within the bladder, rectum, and sexual organs. The vagal and whereas parasympathetic distribution is much more limited. sacral outflows provide motor and secretory fibers to thoracic, abdomi- A preganglionic sympathetic fiber may traverse a considerable distance nal, and pelvic organs (see Figure 10–1). of the sympathetic chain and pass through several ganglia before it  SOMATIC SYSTEM 177 Various levels Motor neuron Skeletal Nicotinic of ACh (striated) Receptors spinal cord muscle Nm Nm AUTONOMIC SYSTEM Parasympathetic Ganglion SECTION II Cranial Muscarinic and ACh Nn Receptors spinal ACh M Smooth M NEUROPHARMACOLOGY muscle, cardiac tissue, Sympathetic secretory Ganglion glands Thoracic Adrenergic and ACh Nn Receptors lumbar NE α /β Nn Sympathetic cholinergic fiber Muscarinic ACh α/β Receptors Adrenal Epi/NE (sweat glands) medulla (80%/20%) ACh M M Sweat glands Figure 10–2 Comparative features of somatic motor nerves and efferent nerves of the autonomic nervous system. The principal neurotransmitters, ACh and NE, are shown in red. The receptors for these transmitters, nicotinic (N) and muscarinic (M) cholinergic receptors, α and β adrenergic receptors, are shown in green. Somatic nerves innervate skeletal muscle directly at a specialized synaptic junction, the motor end plate, where ACh activates Nm receptors. Autonomic nerves innervate smooth muscles, cardiac tissue, and glands. Both parasympathetic and sympathetic systems have ganglia, where ACh is released by the preganglionic fibers; ACh acts on Nn receptors on the postganglionic nerves. ACh is also the neurotransmitter at cells of the adrenal medulla, where it acts on Nn receptors to cause release of EPI and NE into the circulation. ACh is the dominant neurotransmitter released by postganglionic parasympathetic nerves and acts on muscarinic receptors. The ganglia in the parasympathetic system are near or within the organ being innervated, with generally a one-to-one relationship between pre- and postganglionic fibers. NE is the principal neurotransmitter of postganglionic sympathetic nerves, acting on α or β adrenergic receptors. Autonomic nerves form a diffuse pattern with multiple synaptic sites. In the sympathetic system, the ganglia are generally far from the effector cells (e.g., within the sympathetic chain ganglia). Preganglionic sympathetic fibers may make contact with a large number of postganglionic fibers. finally synapses with a postganglionic neuron; also, its terminals make preganglionic axons to ganglion cells may be 1:20 or more; this organi- contact with a large number of postganglionic neurons. The parasym- zation permits diffuse discharge of the sympathetic system. The ratio pathetic system has terminal ganglia very near or within the organs of preganglionic vagal fibers to ganglion cells in the myenteric plexus innervated and is generally more circumscribed in its influences. has been estimated as 1:8000. The cell bodies of somatic motor neurons reside in the ventral horn of the spinal cord; the axon divides into many branches, each of which A Few Details About Innervation innervates a single muscle fiber; more than 100 muscle fibers may be The terminations of the postganglionic autonomic fibers in smooth mus- supplied by one motor neuron to form a motor unit. At each neuro- cle and glands form a rich plexus, or terminal reticulum. The terminal muscular junction (NMJ), the axonal terminal loses its myelin sheath reticulum (sometimes called the autonomic ground plexus) consists of the and forms a terminal arborization that lies in apposition to a special- final ramifications of the postganglionic sympathetic, parasympathetic, ized surface of the muscle membrane, termed the motor end plate (see and visceral afferent fibers, all of which are enclosed within a frequently Figure 13–4). Reciprocal trophic signals between muscle and nerve interrupted sheath of satellite or Schwann cells. At these interruptions, regulate the development of the NMJ (Witzemann et al., 2013). varicosities packed with vesicles are seen in the efferent fibers. Such vari- Ganglionic organization can differ among the different types of nerves cosities occur repeatedly but at variable distances along the course of the and locales. In some organs innervated by the parasympathetic branch, ramifications of the axon. a 1:1 relationship between the number of preganglionic and postgan- “Protoplasmic bridges” occur between the smooth muscle fibers them- glionic fibers has been suggested. In sympathetic ganglia, one ganglion selves at points of contact between their plasma membranes. They are cell may be supplied by several preganglionic fibers, and the ratio of believed to permit the direct conduction of impulses from cell to cell https://ebooksmedicine.net/  178 without the need for chemical transmission. These structures have been General Functions of the Autonomic Nervous System. The auto- termed nexuses, or gap junctions, and they enable the smooth muscle nomic nervous system is the primary regulator of the constancy of the inter- fibers to function as a syncytial unit. nal environment of the organism, or the maintenance of homeostasis. Sympathetic ganglia are extremely complex anatomically and pharma- The sympathetic system and its associated adrenal medulla are not cologically (see Chapter 13). The preganglionic fibers lose their myelin essential to life in a controlled environment, but the lack of sympathoad- sheaths and divide repeatedly into a vast number of end fibers with diam- renal functions becomes evident under circumstances of stress. For exam- eters ranging from 0.1 to 0.3 μm; except at points of synaptic contact, ple, in the absence of the sympathetic system, body temperature cannot they retain their satellite cell sheaths. The vast majority of synapses are be regulated when environmental temperature varies; the concentration axodendritic. Apparently, a given axonal terminal may synapse with mul- of glucose in blood does not rise in response to urgent need; compensa- tiple dendritic processes. tory vascular responses to hemorrhage, oxygen deprivation, excitement, Responses of Effector Organs to Autonomic Nerve Impulses. In and exercise are lacking; and resistance to fatigue is lessened. Sympathetic many instances, the sympathetic and parasympathetic neurotransmitters components of instinctive reactions to the external environment are lost, and other serious deficiencies in the protective forces of the body are CHAPTER 10 NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS can be viewed as physiological or functional antagonists (Table 10–1). Most viscera are innervated by both divisions of the autonomic nervous discernible. The sympathetic system normally is continuously active, the system, and their activities on specific structures may be either discrete degree of activity varying from moment to moment and from organ to and independent or integrated and interdependent. The effects of sympa- organ, adjusting to a constantly changing environment in order to main- thetic and parasympathetic stimulation of the heart and the iris show a tain homeostasis. The sympathoadrenal system can discharge as a unit. pattern of functional antagonism in controlling heart rate and pupillary Heart rate is accelerated; blood pressure rises; blood flow is shifted from aperture, respectively, whereas their actions on male sexual organs are the skin and splanchnic region to the skeletal and cardiac muscles; blood complementary and are integrated to promote sexual function. These glucose rises; the bronchioles and pupils dilate; and the organism is better physiological effects are mediated through negative, and sometimes pos- prepared for “fight or flight.” Many of these effects result primarily from itive, feedback mechanisms. or are reinforced by the actions of EPI secreted by the adrenal medulla. From the responses of the various effector organs to autonomic nerve The parasympathetic system is organized mainly for discrete and local- impulses and the knowledge of the intrinsic autonomic tone, one can pre- ized discharge. Although it is concerned primarily with conservation of dict the actions of drugs that mimic or inhibit the actions of these nerves. energy and maintenance of organ function during periods of minimal HISTORICAL PERSPECTIVE The earliest concrete proposal of a neurohumoral mechanism was “parasympathin”); subsequently, Loewi and Navratil presented evi- made shortly after the turn of the 20th century. Lewandowsky and dence of its identity as ACh. Loewi also discovered that an accelerator Langley independently noted the similarity between the effects of substance similar to EPI and called Acceleranstoff was liberated into injection of extracts of the adrenal gland and stimulation of sym- the perfusion fluid in summer, when the action of the sympathetic pathetic nerves. In 1905, T. R. Elliott, while a student with Langley fibers in the frog’s vagus, a mixed nerve, predominated over that of at Cambridge, postulated that sympathetic nerve impulses release the inhibitory fibers. Feldberg and Krayer demonstrated in 1933 that minute amounts of an EPI-like substance in immediate contact with the cardiac “vagus substance” also is ACh in mammals. effector cells. He considered this substance to be the chemical step In the same year as Loewi’s discovery, Cannon and Uridil reported in the process of transmission. He also noted that long after sym- that stimulation of the sympathetic hepatic nerves resulted in the pathetic nerves had degenerated, the effector organs still responded release of an EPI-like substance that increased blood pressure and characteristically to the hormone of the adrenal medulla. Langley heart rate. Subsequent experiments firmly established that this sub- suggested that effector cells have excitatory and inhibitory “receptive stance is the chemical mediator liberated by sympathetic nerve substances” and that the response to EPI depended on which type impulses at neuroeffector junctions. Cannon called this substance of substance was present. In 1907, Dixon, impressed by the cor- “sympathin.” In many of its pharmacological and chemical properties, respondence between the effects of the alkaloid muscarine and the sympathin closely resembled EPI, but also differed in certain impor- responses to vagal stimulation, advanced the concept that the vagus tant respects. As early as 1910, Barger and Dale noted that the effects nerve liberated a muscarine-like substance that acted as a chemical of sympathetic nerve stimulation were reproduced more closely by transmitter of its impulses. In the same year, Reid Hunt described the the injection of sympathomimetic primary amines than by that of actions of ACh and other choline esters. In 1914, Dale investigated EPI or other secondary amines. The possibility that demethylated EPI the pharmacological properties of ACh and other choline esters and (NE) might be sympathin had been advanced repeatedly, but defin- distinguished its nicotine-like and muscarine-like actions. Intrigued itive evidence for its being the sympathetic nerve mediator was not with the remarkable fidelity with which this drug reproduced the obtained until specific assays were developed for the determination responses to stimulation of parasympathetic nerves, he introduced of sympathomimetic amines in extracts of tissues and body fluids. In the term parasympathomimetic to characterize its effects. Dale also 1946, von Euler found that the sympathomimetic substance in highly noted the brief duration of action of this chemical and proposed that purified extracts of bovine splenic nerve resembled NE by all criteria an esterase in the tissues rapidly splits ACh to acetic acid and choline, used (von Euler, 1946). thereby terminating its action. We now know that NE is the predominant sympathomimetic sub- The studies of Loewi, begun in 1921, provided the first direct evi- stance in the postganglionic sympathetic nerves of mammals and is the dence for the chemical mediation of nerve impulses by the release of adrenergic mediator liberated by their stimulation. NE, its immediate specific chemical agents. Loewi stimulated the vagus nerve of a per- precursor dopamine (DA), and its N-methylated derivative EPI also are fused (donor) frog heart and allowed the perfusion fluid to come in neurotransmitters in the CNS (see Chapter 16). As for ACh, in addition contact with a second (recipient) frog heart used as a test object. The to its role as the transmitter of most postganglionic parasympathetic recipient frog heart was found to respond, after a short lag, in the fibers and of a few postganglionic sympathetic fibers, ACh functions as same way as the donor heart. It thus was evident that a substance was a neurotransmitter in three additional classes of nerves: preganglionic liberated from the first organ that slowed the rate of the second. Loewi fibers of both the sympathetic and the parasympathetic systems, motor referred to this chemical substance as Vagusstoff (“vagus substance,” nerves to skeletal muscle, and certain neurons within the CNS.  179 TABLE 10–1 RESPONSES OF EFFECTOR ORGANS TO AUTONOMIC NERVE IMPULSES ADRENERGIC PARASYMPATHETIC CHOLINERGIC ORGAN SYSTEM SYMPATHETIC EFFECTa RECEPTOR SUBTYPEb EFFECTa RECEPTOR SUBTYPEb Eye Radial muscle, iris pupillary Contraction (mydriasis)++ α1 dilator (dilator pupillae) Sphincter muscle, iris Contraction (miosis)+++ M3, M2 pupillary constrictor (sphincter pupillae) Ciliary muscle Relaxation for far vision+ β2 Contraction for near M3, M2 SECTION II vision+++ Lacrimal glands Secretion+ α Secretion+++ M3, M2 Heart c Sinoatrial node ↑ heart rate++ β1 > β2 ↓ heart rate+++ M2 >> M3 Atria ↑ contractility and conduction β1 > β2 ↓ contractility++ and M2 >> M3 NEUROPHARMACOLOGY velocity++ shortened AP duration Atrioventricular node ↑ automaticity and conduction β1 > β2 ↓ conduction velocity; AV M2 >> M3 velocity++ block+++ His-Purkinje system ↑ automaticity and conduction β1 > β2 Little effect M2 >> M3 velocity Ventricle ↑ contractility, conduction β1 > β2 Slight ↓ in contractility M2 >> M3 velocity, automaticity, and rate of idioventricular pacemakers+++ Blood vessels Arteries and arteriolesd Coronary Constriction+; dilatione++ α1, α2; β2 No innervationh — Skin and mucosa Constriction+++ α1, α2 No innervation h — Skeletal muscle Constriction; dilatione,f++ α1; β2 Dilationh (?) — Cerebral Constriction (slight) α1 No innervation h — Pulmonary Constriction+; dilation α1; β2 No innervationh — Abdominal viscera Constriction+++; dilation+ α1; β2 No innervationh — Salivary glands Constriction+++ α1, α2 Dilation ++ h M3 Renal Constriction++; dilation++ α1, α2; β1, β2 No innervationh (Veins)d Constriction; dilation α1, α2; β2 Endothelium — — ↑ NO synthaseh M3 Lung Tracheal and bronchial Relaxation β2 Contraction M2 = M3 smooth muscle Bronchial glands ↓ secretion, ↑ secretion α1 Stimulation M2, M3 β2 Stomach Motility and tone ↓ (usually)i+ α1, α2, β1, β2 ↑i+++ M2 = M3 Sphincters Contraction (usually)+ α1 Relaxation (usually)+ M3, M2 Secretion Inhibition α2 Stimulation++ M3, M2 Intestine Motility and tone Decreaseh+ α1, α2, β1, β2 ↑i+++ M3, M2 Sphincters Contraction+ α1 Relaxation (usually)+ M3, M2 Secretion ↓ α2 ↑++ M3, M2 Gallbladder and ducts Relaxation+ β2 Contraction+ M kidney Renin secretion ↓+; ↑++ α1; β1 No innervation — Urinary bladder Detrusor Relaxation+ β2 Contraction+++ M3 > M2 https://ebooksmedicine.net/ (Continued)  180 TABLE 10–1 RESPONSES OF EFFECTOR ORGANS TO AUTONOMIC NERVE IMPULSES (CONTINUED) ADRENERGIC PARASYMPATHETIC CHOLINERGIC ORGAN SYSTEM SYMPATHETIC EFFECTa RECEPTOR SUBTYPEb EFFECTa RECEPTOR SUBTYPEb Trigone and sphincter Contraction++ α1 Relaxation++ M3 > M2 Ureter Motility and tone ↑ α1 ↑ (?) M Uterus Pregnant contraction α1 Relaxation β2 Variablej M Nonpregnant relaxation β2 CHAPTER 10 NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS Sex organs, male skin Ejaculation+++ α1 Erection+++ M3 Pilomotor muscles Contraction++ α1 — Sweat glands Localized secretionk++ α1 — — Generalized secretion+++ M3, M2 Spleen capsule Contraction+++ α1 — — Relaxation+ β2 — Adrenal medulla — Secretion of EPI and NE N (α3)2(β4)3; M (secondarily) Skeletal muscle Increased contractility; β2 — — glycogenolysis; K+ uptake Liver Glycogenolysis and α1 — — gluconeogenesis+++ β2 Pancreas Acini ↓ secretion+ α Secretion++ M3, M2 Islets (β cells) ↓ secretion+++ α2 — ↑ secretion+ β2 Fat cellsl Lipolysis+++; thermogenesis α1, β1, β2, β3 — — Inhibition of lipolysis α2 Salivary glands K+ and water secretion+ α1 K+ and water M3, M2 secretion+++ Nasopharyngeal glands — Secretion++ M3, M2 Pineal glands Melatonin synthesis β — Posterior pituitary ADH secretion β1 — Autonomic nerve endings Sympathetic terminal Autoreceptor Inhibition of NE release α2A > α2C(α2B) Heteroreceptor — Inhibition of NE release M2, M4 Parasympathetic terminal Autoreceptor — — Inhibition of ACh release M2, M4 Heteroreceptor Inhibition ACh release α2A > α2C — — a Responses are designated + to +++ to provide an approximate indication of the importance of sympathetic and parasympathetic nerve activity in the control of the various organs and functions listed. b Adrenergic receptors: α1, α2 and subtypes thereof; β1, β2, β3. Cholinergic receptors: nicotinic (N); muscarinic (M), with subtypes 1–4. The receptor subtypes are described more fully in Chapters 11 and 14 and in Tables 10–2, 10–3, 10–6, and 10–7. When a designation of subtype is not provided, the nature of the subtype has not been determined unequivocally. Only the principal receptor subtypes are shown. Transmitters other than ACh and NE contribute to many of the responses. c In the human heart, the ratio of β1 to β2 is about 3:2 in atria and 4:1 in ventricles. While M2 receptors predominate, M3 receptors are also present. d The predominant α1 receptor subtype in most blood vessels (both arteries and veins) is α1A, although other α1 subtypes are present in specific blood vessels. The α1D is the predominant subtype in the aorta. e Dilation predominates in situ owing to metabolic autoregulatory mechanisms. f Over the usual concentration range of physiologically released circulating EPI, the β receptor response (vasodilation) predominates in blood vessels of skeletal muscle and liver; β receptor response (vasoconstriction) predominates in blood vessels of other abdominal viscera. The renal and mesenteric vessels also contain specific dopaminergic receptors whose activation causes dilation. g Sympathetic cholinergic neurons cause vasodilation in skeletal muscle beds, but this is not involved in most physiological responses. h The endothelium of most blood vessels releases NO, which causes vasodilation in response to muscarinic stimuli. However, unlike the receptors innervated by sympathetic cholinergic fibers in skeletal muscle blood vessels, these muscarinic receptors are not innervated and respond only to exogenously added muscarinic agonists in the circulation. i While adrenergic fibers terminate at inhibitory β receptors on smooth muscle fibers and at inhibitory β receptors on parasympathetic (cholinergic) excitatory ganglion cells of the myenteric plexus, the primary inhibitory response is mediated via enteric neurons through NO, P2Y receptors, and peptide receptors. j Uterine responses depend on stages of menstrual cycle, amount of circulating estrogen and progesterone, and other factors.