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Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System

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ABSTRACT

Comprised of the sympathetic nervous system, parasympathetic nervous system, and enteric nervous system, the autonomic nervous system (ANS) provides the neural control of all parts of the body except for skeletal muscles. The ANS has the major responsibility to ensure that the physiological integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) in the face of perturbations exerted by both the external and internal environments. Many commonly prescribed drugs, over‐the‐counter drugs, toxins, and toxicants function by altering transmission within the ANS. Autonomic dysfunction is a signature of many neurological diseases or disorders. Despite the physiological relevance of the ANS, most neuroscience textbooks offer very limited coverage of this portion of the nervous system. This review article provides both historical and current information about the anatomy, physiology, and pharmacology of the sympathetic and parasympathetic divisions of the ANS. The ultimate aim is for this article to be a valuable resource for those interested in learning the basics of these two components of the ANS and to appreciate its importance in both health and disease. Other resources should be consulted for a thorough understanding of the third division of the ANS, the enteric nervous system. © 2016 American Physiological Society. Compr Physiol 6:1239‐1278, 2016.

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Figure 1. Figure 1. Schematic of the ANS showing the distribution of sympathetic (left) and parasympathetic nerves (right) in vertebrates. Sympathetic preganglionic neurons are primarily located in the first thoracic through the first few lumbar spinal segments, which explains why it is also called the thoracolumbar division of the ANS. In some species, there are also preganglionic neurons located in the caudal portion of the eighth cervical segment (shown as a dashed line). Paravertebral sympathetic ganglia (located adjacent to the vertebral column) are “connected” via the axons of the preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance, forming the sympathetic chain. Parasympathetic preganglionic neurons are located in several cranial nerve nuclei (III, VII, IX, and X) and in the sacral spinal cord, which explains why it is also called the craniosacral division of the ANS. Postganglionic parasympathetic neurons are located close to or within the target organ. Visceral sensory afferents that are intermingled with parasympathetic efferent fibers in the thoracic, abdominal, and pelvic cavities are also shown. These afferent fibers synapse in the nucleus of the tractus solitarius (NTS) in the brainstem. Cranial nerve nuclei I, VII, and IX and sacral parasympathetic nerves also contain visceral sensory fibers (not shown). Visceral sensory afferents are also intermingled with sympathetic efferent fibers as shown in Figure . Cholinergic neurons are shown in black; noradrenergic neurons are shown in red; visceral sensory fibers are shown in gray.
Figure 2. Figure 2. Projections of sympathetic preganglionic neurons to paravertebral or prevertebral ganglia or the adrenal medulla. The axons of sympathetic preganglionic neurons leave the spinal cord at the segment of origin of their cell bodies within the IML column. These fibers exit via the ventral root with the axons of α‐ and γ‐motor neurons; sympathetic preganglionic fibers separate from the ventral root to form the white ramus to then terminate on postganglionic neurons in the adjacent or distant paravertebral ganglia or in prevertebral ganglia in the he abdominal and pelvic region. Another possible trajectory is to terminate on chromaffin cells in the adrenal medulla (not shown). Visceral sensory afferents are intermingled with sympathetic efferent fibers and travel with somatic afferents via the dorsal root to terminate in the spinal cord dorsal horn. Preganglionic nerves are shown in red, postganglionic nerves are shown in black, visceral sensory afferents are shown in blue, and somatic afferents are shown in green.
Figure 3. Figure 3. The biochemical events at a cholinergic autonomic neuroeffector junction such as autonomic ganglia, smooth muscle, glands, or the heart. Choline is transported into the presynaptic nerve terminal by a Na+‐dependent choline transporter. ACh is synthesized from choline and acetyl Co‐A (AcCoA) by the enzyme choline acetyltransferase (ChAT). ACh is transported from the cytoplasm into vesicles by the vesicular transporter along with peptides (P) and adenosine triphosphate (ATP). ACh is released from the nerve terminal in response to an action potential‐mediated influx of Ca2+. This causes the vesicles to fuse with the surface membrane; vesicle‐associated membrane proteins (VAMPs) promote the alignment of the vesicles with the release site on the inner membrane of the nerve terminal. ACh and cotransmitters are released into the synaptic cleft via a process that includes synaptosome‐associated proteins (SNAPs). The released ACh can act on muscarinic (M1‐M5) G protein‐coupled receptors on the postsynaptic target (e.g., smooth muscle) or on nicotinic ionotropic receptors in autonomic ganglia (NN). In the synaptic junction, ACh is readily metabolized by the enzyme acetylcholinesterase. Autoreceptors and heteroreceptors on the presynaptic nerve ending modulate neurotransmitter release.
Figure 4. Figure 4. The biochemical events at a noradrenergic sympathetic neuroeffector junction such smooth muscle, glands, or the heart. Tyrosine is transported into the nerve terminal by a tyrosine transporter. See Figure for the sequential steps involved in the conversion of tyrosine to 3,4‐dihydroxy‐l‐phenylalanine (DOPA) to dopamine (DA) to NE. DA is transported from the cytoplasm into the vesicle by the vesicular monoamine transporter (VMAT) and is then converted to NE in the vesicle. NE is released from the nerve terminal in response to an action potential‐mediated influx of Ca2+; vesicles then fuse with the surface membrane to trigger expulsion of NE and cotransmitters such as ATP and neuropeptide Y (NPY). The process involves SNAPs and VAMPs. The released NE and cotransmitters can act on either G protein‐coupled or ligand‐gated ion channel receptors on the sympathetic neuroeffector organ. NE can also diffuse out of the cleft or be transported back into the nerve terminal by the NET. Transmitter release is modulated by autoreceptors and heteroreceptors on the presynaptic nerve terminal.
Figure 5. Figure 5. Steps involved in the synthesis and metabolism of catecholamines. The enzymes involved in the synthesis of DOPA, dopamine, NE, and epinephrine from tyrosine are shown in green. The two enzymes involved in the degradation of catecholamines are monoamine oxidase (MAO) and catechol‐O‐methyltransferase (COMT). MAO converts NE and epinephrine to a reactive intermediate aldehyde metabolite, 3,4‐dihydroxyphenylglycolaldehyde (DOPEGAL) which is then converted via an aldehyde reductase (AR) to 3,4‐dihydroxyphenylglycol (DHPG) or via an aldehyde dehydrogenase (AD) to 3, 4‐dihydroxymandelic acid (DHMA). DHPG is then converted to 3‐methoxy,4‐hydroxyphenylglycol (MHPG) by COMT. MHPG is converted to 3‐methoxy‐4‐hydroxyphenylglycolaldehyde (MOPEGAL) by an alcohol dehydrogenase (ADH). MOPEGAL is then converted to vanillylmandelic acid (VMA) by AD; VMA is the most plentiful catecholamine metabolite in the urine of humans. A minor pathway involved in the formation of VMA includes the action of COMT to convert NE (or epinephrine) to normetanephrine (or metanephrine) which is then converted to MOPEGAL by MAO. The thickness of the red lines signifies the importance of the metabolic step.


Figure 1. Schematic of the ANS showing the distribution of sympathetic (left) and parasympathetic nerves (right) in vertebrates. Sympathetic preganglionic neurons are primarily located in the first thoracic through the first few lumbar spinal segments, which explains why it is also called the thoracolumbar division of the ANS. In some species, there are also preganglionic neurons located in the caudal portion of the eighth cervical segment (shown as a dashed line). Paravertebral sympathetic ganglia (located adjacent to the vertebral column) are “connected” via the axons of the preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance, forming the sympathetic chain. Parasympathetic preganglionic neurons are located in several cranial nerve nuclei (III, VII, IX, and X) and in the sacral spinal cord, which explains why it is also called the craniosacral division of the ANS. Postganglionic parasympathetic neurons are located close to or within the target organ. Visceral sensory afferents that are intermingled with parasympathetic efferent fibers in the thoracic, abdominal, and pelvic cavities are also shown. These afferent fibers synapse in the nucleus of the tractus solitarius (NTS) in the brainstem. Cranial nerve nuclei I, VII, and IX and sacral parasympathetic nerves also contain visceral sensory fibers (not shown). Visceral sensory afferents are also intermingled with sympathetic efferent fibers as shown in Figure . Cholinergic neurons are shown in black; noradrenergic neurons are shown in red; visceral sensory fibers are shown in gray.


Figure 2. Projections of sympathetic preganglionic neurons to paravertebral or prevertebral ganglia or the adrenal medulla. The axons of sympathetic preganglionic neurons leave the spinal cord at the segment of origin of their cell bodies within the IML column. These fibers exit via the ventral root with the axons of α‐ and γ‐motor neurons; sympathetic preganglionic fibers separate from the ventral root to form the white ramus to then terminate on postganglionic neurons in the adjacent or distant paravertebral ganglia or in prevertebral ganglia in the he abdominal and pelvic region. Another possible trajectory is to terminate on chromaffin cells in the adrenal medulla (not shown). Visceral sensory afferents are intermingled with sympathetic efferent fibers and travel with somatic afferents via the dorsal root to terminate in the spinal cord dorsal horn. Preganglionic nerves are shown in red, postganglionic nerves are shown in black, visceral sensory afferents are shown in blue, and somatic afferents are shown in green.


Figure 3. The biochemical events at a cholinergic autonomic neuroeffector junction such as autonomic ganglia, smooth muscle, glands, or the heart. Choline is transported into the presynaptic nerve terminal by a Na+‐dependent choline transporter. ACh is synthesized from choline and acetyl Co‐A (AcCoA) by the enzyme choline acetyltransferase (ChAT). ACh is transported from the cytoplasm into vesicles by the vesicular transporter along with peptides (P) and adenosine triphosphate (ATP). ACh is released from the nerve terminal in response to an action potential‐mediated influx of Ca2+. This causes the vesicles to fuse with the surface membrane; vesicle‐associated membrane proteins (VAMPs) promote the alignment of the vesicles with the release site on the inner membrane of the nerve terminal. ACh and cotransmitters are released into the synaptic cleft via a process that includes synaptosome‐associated proteins (SNAPs). The released ACh can act on muscarinic (M1‐M5) G protein‐coupled receptors on the postsynaptic target (e.g., smooth muscle) or on nicotinic ionotropic receptors in autonomic ganglia (NN). In the synaptic junction, ACh is readily metabolized by the enzyme acetylcholinesterase. Autoreceptors and heteroreceptors on the presynaptic nerve ending modulate neurotransmitter release.


Figure 4. The biochemical events at a noradrenergic sympathetic neuroeffector junction such smooth muscle, glands, or the heart. Tyrosine is transported into the nerve terminal by a tyrosine transporter. See Figure for the sequential steps involved in the conversion of tyrosine to 3,4‐dihydroxy‐l‐phenylalanine (DOPA) to dopamine (DA) to NE. DA is transported from the cytoplasm into the vesicle by the vesicular monoamine transporter (VMAT) and is then converted to NE in the vesicle. NE is released from the nerve terminal in response to an action potential‐mediated influx of Ca2+; vesicles then fuse with the surface membrane to trigger expulsion of NE and cotransmitters such as ATP and neuropeptide Y (NPY). The process involves SNAPs and VAMPs. The released NE and cotransmitters can act on either G protein‐coupled or ligand‐gated ion channel receptors on the sympathetic neuroeffector organ. NE can also diffuse out of the cleft or be transported back into the nerve terminal by the NET. Transmitter release is modulated by autoreceptors and heteroreceptors on the presynaptic nerve terminal.


Figure 5. Steps involved in the synthesis and metabolism of catecholamines. The enzymes involved in the synthesis of DOPA, dopamine, NE, and epinephrine from tyrosine are shown in green. The two enzymes involved in the degradation of catecholamines are monoamine oxidase (MAO) and catechol‐O‐methyltransferase (COMT). MAO converts NE and epinephrine to a reactive intermediate aldehyde metabolite, 3,4‐dihydroxyphenylglycolaldehyde (DOPEGAL) which is then converted via an aldehyde reductase (AR) to 3,4‐dihydroxyphenylglycol (DHPG) or via an aldehyde dehydrogenase (AD) to 3, 4‐dihydroxymandelic acid (DHMA). DHPG is then converted to 3‐methoxy,4‐hydroxyphenylglycol (MHPG) by COMT. MHPG is converted to 3‐methoxy‐4‐hydroxyphenylglycolaldehyde (MOPEGAL) by an alcohol dehydrogenase (ADH). MOPEGAL is then converted to vanillylmandelic acid (VMA) by AD; VMA is the most plentiful catecholamine metabolite in the urine of humans. A minor pathway involved in the formation of VMA includes the action of COMT to convert NE (or epinephrine) to normetanephrine (or metanephrine) which is then converted to MOPEGAL by MAO. The thickness of the red lines signifies the importance of the metabolic step.
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How to Cite

Erica A. Wehrwein, Hakan S. Orer, Susan M. Barman. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. Compr Physiol 2016, 6: 1239-1278. doi: 10.1002/cphy.c150037