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Introduction to Autonomic Pharmacology:
Chemical transmission in the ANS
(cholinergic and adrenergic)
(PC-630)
Dr. Bidya Dhar Sahu
Nervous System
INTRODUCTION
A. Visceral Afferent Fibers:
qInformation on the status of the visceral organs is transmitted to the CNS through
two main sensory systems:
§ the cranial nerve (parasympathetic) visceral sensory system and
§ the spinal (sympathetic) visceral afferent system.
qCranial visceral sensory information enters the CNS by four cranial nerves: the
trigeminal (V), facial (VII), glossopharyngeal (IX), and vagus (X) nerves.
qThese four cranial nerves transmit visceral sensory information from the internal
face and head (V); tongue (taste, VII); hard palate and upper part of the
oropharynx (IX); and carotid body, lower part of the oropharynx, larynx, trachea,
esophagus, and thoracic and abdominal organs (X), with the exception of the
pelvic viscera. The pelvic viscera are innervated by nerves from the second
through fourth sacral spinal segments.
In body, nerve fibers are divided in to following types:
B. Visceral Efferent Fibers:
On the efferent side, Information on the status of the CNS/Spinal Cord is transmitted to the visceral
organs.
The neurons consists of two large divisions:
(1) the sympathetic or thoracolumbar outflow
(2) the parasympathetic or craniosacral outflow.
Autonomic Nervous System (ANS):
§ Also called as Visceral, vegetative or involuntary nervous system
§ Regulates all autonomic functions that occur without conscious control
§ The autonomic nervous system conveys all the outputs from the CNS to the
rest of the body, except for the motor innervation of skeletal muscle.
§ The terms cholinergic and adrenergic describe neurons that liberate
Acetylcholine (Ach) or Norepinephrine (NE), respectively.
§ ANS consists of three main anatomical divisions:
1. Sympathetic NS
2. Parasympathetic NS
3. Enteric NS
A. Sympathetic Nervous System: ‘fight or flight’ state
q The cell bodies of the sympathetic preganglionic neurons lie in the lateral horn of the grey
matter of the thoracic and lumbar segments of the spinal cord, and the fibres leave the spinal
cord in the spinal nerves as the thoracolumbar sympathetic outflow.
q The intervening synapses lie in autonomic ganglia, which are outside the CNS, and contain
the nerve endings of preganglionic fibres and the cell bodies of postganglionic neurons.
q Sympathetic ganglia are found in three locations: paravertebral, prevertebral, and terminal.
q The white rami are restricted to the segments of the thoracolumbar outflow; they carry the
preganglionic myelinated fibers that exit the spinal cord by the anterior spinal roots.
q The gray rami arise from the ganglia and carry postganglionic fibers back to the spinal
nerves for distribution to effector organ.
Wehrwein et al., 2016, Compr Physiol 6:1239-1278, 2016.
Diagrammatical Presentation:
A. Sympathetic Nervous System:
q The 22 pairs of paravertebral sympathetic ganglia form the lateral chains on either side of
the vertebral column. The ganglia are connected to each other by nerve trunks and to the
spinal nerves by rami communicantes.
q The prevertebral ganglia lie in the abdomen and the pelvis near the ventral surface of the
bony vertebral column and consist mainly of the celiac (solar), superior mesenteric,
aorticorenal, and inferior mesenteric ganglia.
q The terminal ganglia are few in number, lie near the organs they innervate, and include
ganglia connected with the urinary bladder and rectum and the cervical ganglia in the
region of the neck.
q Preganglionic fibers issuing from the spinal cord may synapse with the neurons of more
than one sympathetic ganglion, and Postganglionic fibers arising from sympathetic ganglia
innervate visceral structures of the thorax, abdomen, head, and neck.
B. Parasympathetic Nervous System: ‘rest and digest’ state
q The parasympathetic nervous system consists of preganglionic fibers that
originate in the CNS and their postganglionic connections.
q In parasympathetic pathways, the postganglionic cells are mainly found in the
target organs.
q The parasympathetic system is connected to the CNS via:
§ cranial nerve outflow (III, VII, IX, X) [Oculomotor nerve (III) (carrying
parasympathetic fibres destined for the eye), the facial (VII) (carrying fibres to the
salivary glands), glossopharyngeal nerves (IX) (carrying fibres to the
nasopharynx) and the vagus nerve (X) (carrying fibres to the thoracic and
abdominal viscera)]
§ sacral outflow [destined for the pelvic and abdominal viscera emerge in a bundle
of nerves known as the nervi erigentes]
C. Enteric Nervous System (ENS):
q The processes of mixing, propulsion, and absorption of nutrients in the GI tract are
controlled locally through a restricted part of the peripheral nervous system called the
ENS.
q The ENS comprises components of the sympathetic and parasympathetic nervous systems
and has sensory nerve connections through the spinal and nodose ganglia.
q Two nerve plexuses: (i) the myenteric (Auerbach) plexus and
(ii) the submucosal (Meissner) plexus.
q The myenteric plexus, located between the longitudinal and circular muscle layers, plays
an important role in the contraction and relaxation of GI smooth muscle.
q The submucosal plexus is involved with secretory and absorptive functions of the GI
epithelium, local blood flow, and neuroimmune activities.
q Neurotransmitters of ENS: ACh, ATP, Substance P, 5-HT.
Difference between Sympathetic and Parasympathetic Nervous System
q Autonomic nervous system supply all innervated structures of the body except
skeletal muscle, which is served by somatic nerves.
q The most autonomic ganglia that are entirely outside the cerebrospinal axis.
Somatic nerves contain no peripheral ganglia, and the synapses are located
entirely within the cerebrospinal axis.
q Many autonomic nerves form extensive peripheral plexuses; such networks are
absent from the somatic system.
q Postganglionic autonomic nerves generally are nonmyelinated; motor nerves to
skeletal muscles are myelinated.
q When the spinal efferent nerves are interrupted, smooth muscles and glands
generally retain some level of spontaneous activity, whereas the denervated
skeletal muscles are paralyzed.
Difference between Autonomic and Somatic Nervous System
Neurochemical transmission:
Steps Involved in Neurotransmission:
1. Axonal Conduction
2. Junctional Transmission
i. Storage and release of transmitter
ii. Interaction of the transmitter with postjunctional receptors
and production of the postjunctional potential
iii. Initiation of postjunctional activity
iv. Destruction or dissipation of the transmitter
v. Nonelectrogenic functions
1. Axonal Conduction
1. Axonal Conduction
q Conduction refers to the passage of an electrical impulse along an axon or muscle fiber.
q At rest, the interior of the typical mammalian axon is about 70 mV negative to the exterior.
q In response to depolarization to a threshold level, an action potential (AP) is initiated at a local region of the
membrane.
q The AP consists of two phases. Following depolarization that induces an open conformation of the channel, the
initial phase is caused by a rapid increase in the permeability and inward movement of Na+ through voltage-
sensitive Na+ channels, and a rapid depolarization from the resting potential continues to a positive overshoot.
q The second phase results from the rapid inactivation of the Na+ channel and the delayed opening of a K+ channel,
which permits outward movement of K+ to terminate the depolarization.
q Although not important in axonal conduction, Ca2+ channels in other tissues (e.g., L-type Ca2+ channels in heart)
contribute to the AP by prolonging depolarization by an inward movement of Ca2+.
q This influx of Ca2+ also serves as a stimulus to initiate intracellular events, and Ca2+ influx is important in
excitation-exocytosis coupling (transmitter release).
q The transmembrane ionic currents produce local circuit currents such that adjacent resting channels in the axon
are activated, and excitation of an adjacent portion of the axonal membrane occurs, leading to propagation of the
AP without decrement along the axon.
1. Axonal Conduction
2. Junctional Transmission
Goodman and Gillman Book _The Pharmacological
Basis of Therapeutics_13th
Edition, 2017
q Transmission refers to the passage of an impulse across a synaptic or neuroeffector junction.
q The arrival of the action potential at the axonal terminals initiates a series of events that trigger transmission of
an excitatory or inhibitory biochemical message across the synapse or neuroeffector junction.
i. Storage and release of transmitter:
§ The nonpeptide (small-molecule) neurotransmitters, such as biogenic amines, are largely synthesized in
the region of the axonal terminals and stored there in synaptic vesicles.
§ Neurotransmitter transport into storage vesicles is driven by an electrochemical gradient generated by the
vesicular proton pump (vesicular ATPase).
§ Synaptic vesicles cluster in discrete areas underlying the presynaptic plasma membrane, termed active
zones, often aligning with the tips of postsynaptic folds. Proteins in the vesicular membrane (e.g., synapsin,
synaptophysin, synaptogyrin) are involved in development and trafficking of the storage vesicle to the
active zone.
§ The processes of priming, docking, fusion, and exocytosis involve the interactions of proteins in the
vesicular and plasma membranes and the rapid entry of extracellular Ca2+ and its binding to
synaptotagmins.
2. Junctional Transmission
Molecular basis of exocytosis: Docking and fusion of
synaptic vesicles with neuronal membranes:
1. Vesicular docking in the active zone: Munc18
binds to syntaxin 1, stabilizing the neuronal
membrane SNARE proteins.
2. Priming I: Syntaxin assembles with SNAP25,
allowing for the vesicle SNARE protein
synaptobrevin to bind to the complex.
3. Priming II: Complexin binds to the SNARE
complex and allows for the vesicular
synaptotagmin to bind Ca2+ that drives the full
fusion process.
4. Fusion pore opening: Synaptotagmin interacts
with the SNARE complex and binds Ca2+,
permitting pore fusion and exocytosis of
neurotransmitter.
5. Return to ground state: After fusion, the
chaperone ATPase NSF and its SNAP adapters
catalyze dissociation of the SNARE-complex
2. Junctional Transmission
ii. Interaction of the transmitter with postjunctional receptors and production of the
postjunctional potential:
§ The transmitter diffuses across the synaptic or junctional cleft and combines with
specialized receptors on the postjunctional membrane; this often results in a localized
increase in the ionic permeability, or conductance, of the membrane.
§ One of three types of permeability change can occur:
-Generalized increase in the permeability to cations (notably Na+ but occasionally
Ca2+), resulting in a localized depolarization of the membrane, that is, an EPSP.
-Selective increase in permeability to anions, usually Cl–, resulting in stabilization or
actual hyperpolarization of the membrane, which constitutes an IPSP.
-Increased permeability to K+. Because the K+ gradient is directed out of the cell,
hyperpolarization and stabilization of the membrane potential occur (an IPSP).
2. Junctional Transmission
iii. Initiation of postjunctional activity:
§ If an EPSP exceeds a certain threshold value, it initiates a propagated action
potential in a postsynaptic neuron or a muscle action potential in skeletal or
cardiac muscle by activating voltage-sensitive channels in the immediate vicinity.
§ An IPSP, which is found in neurons and smooth muscle but not in skeletal
muscle, will tend to oppose excitatory potentials simultaneously initiated by other
neuronal sources.
§ Whether a propagated impulse or other response ensues depends on the
summation of all the potentials.
2. Junctional Transmission
iv. Destruction or dissipation of the transmitter:
§ When impulses can be transmitted across junctions at frequencies up to several hundred
per second, there must be an efficient means of disposing of the transmitter following each
impulse.
§ At cholinergic synapses involved in rapid neurotransmission, high and localized
concentrations of Acetylcholinesterase (AChE) are available for this purpose. When AChE
activity is inhibited, removal of the transmitter is accomplished principally by diffusion.
§ Rapid termination of Norepinephrine (NE) occurs by a combination of simple diffusion and
reuptake by the axonal terminals of most of the released NE.
§ Termination of the action of amino acid transmitters results from their active transport into
neurons and surrounding glia.
§ Peptide neurotransmitters are hydrolyzed by various peptidases and dissipated by
diffusion.
2. Junctional Transmission
v. Nonelectrogenic functions:
The activity and turnover of enzymes involved in the synthesis and inactivation
of neurotransmitters, the density of presynaptic and postsynaptic receptors, and
other characteristics of synapses are controlled by trophic actions of
neurotransmitters or other trophic factors released by the neuron or target cells.
2. Junctional Transmission
Rang and Dale’s Pharmacology Book, 9th Edition,2019
Thank you

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ANS_Introduction to Autonomic Anatomy.pdf

  • 1. Introduction to Autonomic Pharmacology: Chemical transmission in the ANS (cholinergic and adrenergic) (PC-630) Dr. Bidya Dhar Sahu
  • 3. A. Visceral Afferent Fibers: qInformation on the status of the visceral organs is transmitted to the CNS through two main sensory systems: § the cranial nerve (parasympathetic) visceral sensory system and § the spinal (sympathetic) visceral afferent system. qCranial visceral sensory information enters the CNS by four cranial nerves: the trigeminal (V), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. qThese four cranial nerves transmit visceral sensory information from the internal face and head (V); tongue (taste, VII); hard palate and upper part of the oropharynx (IX); and carotid body, lower part of the oropharynx, larynx, trachea, esophagus, and thoracic and abdominal organs (X), with the exception of the pelvic viscera. The pelvic viscera are innervated by nerves from the second through fourth sacral spinal segments. In body, nerve fibers are divided in to following types:
  • 4. B. Visceral Efferent Fibers: On the efferent side, Information on the status of the CNS/Spinal Cord is transmitted to the visceral organs. The neurons consists of two large divisions: (1) the sympathetic or thoracolumbar outflow (2) the parasympathetic or craniosacral outflow.
  • 5. Autonomic Nervous System (ANS): § Also called as Visceral, vegetative or involuntary nervous system § Regulates all autonomic functions that occur without conscious control § The autonomic nervous system conveys all the outputs from the CNS to the rest of the body, except for the motor innervation of skeletal muscle. § The terms cholinergic and adrenergic describe neurons that liberate Acetylcholine (Ach) or Norepinephrine (NE), respectively. § ANS consists of three main anatomical divisions: 1. Sympathetic NS 2. Parasympathetic NS 3. Enteric NS
  • 6. A. Sympathetic Nervous System: ‘fight or flight’ state q The cell bodies of the sympathetic preganglionic neurons lie in the lateral horn of the grey matter of the thoracic and lumbar segments of the spinal cord, and the fibres leave the spinal cord in the spinal nerves as the thoracolumbar sympathetic outflow. q The intervening synapses lie in autonomic ganglia, which are outside the CNS, and contain the nerve endings of preganglionic fibres and the cell bodies of postganglionic neurons. q Sympathetic ganglia are found in three locations: paravertebral, prevertebral, and terminal. q The white rami are restricted to the segments of the thoracolumbar outflow; they carry the preganglionic myelinated fibers that exit the spinal cord by the anterior spinal roots. q The gray rami arise from the ganglia and carry postganglionic fibers back to the spinal nerves for distribution to effector organ.
  • 7. Wehrwein et al., 2016, Compr Physiol 6:1239-1278, 2016.
  • 9. A. Sympathetic Nervous System: q The 22 pairs of paravertebral sympathetic ganglia form the lateral chains on either side of the vertebral column. The ganglia are connected to each other by nerve trunks and to the spinal nerves by rami communicantes. q The prevertebral ganglia lie in the abdomen and the pelvis near the ventral surface of the bony vertebral column and consist mainly of the celiac (solar), superior mesenteric, aorticorenal, and inferior mesenteric ganglia. q The terminal ganglia are few in number, lie near the organs they innervate, and include ganglia connected with the urinary bladder and rectum and the cervical ganglia in the region of the neck. q Preganglionic fibers issuing from the spinal cord may synapse with the neurons of more than one sympathetic ganglion, and Postganglionic fibers arising from sympathetic ganglia innervate visceral structures of the thorax, abdomen, head, and neck.
  • 10.
  • 11. B. Parasympathetic Nervous System: ‘rest and digest’ state q The parasympathetic nervous system consists of preganglionic fibers that originate in the CNS and their postganglionic connections. q In parasympathetic pathways, the postganglionic cells are mainly found in the target organs. q The parasympathetic system is connected to the CNS via: § cranial nerve outflow (III, VII, IX, X) [Oculomotor nerve (III) (carrying parasympathetic fibres destined for the eye), the facial (VII) (carrying fibres to the salivary glands), glossopharyngeal nerves (IX) (carrying fibres to the nasopharynx) and the vagus nerve (X) (carrying fibres to the thoracic and abdominal viscera)] § sacral outflow [destined for the pelvic and abdominal viscera emerge in a bundle of nerves known as the nervi erigentes]
  • 12. C. Enteric Nervous System (ENS): q The processes of mixing, propulsion, and absorption of nutrients in the GI tract are controlled locally through a restricted part of the peripheral nervous system called the ENS. q The ENS comprises components of the sympathetic and parasympathetic nervous systems and has sensory nerve connections through the spinal and nodose ganglia. q Two nerve plexuses: (i) the myenteric (Auerbach) plexus and (ii) the submucosal (Meissner) plexus. q The myenteric plexus, located between the longitudinal and circular muscle layers, plays an important role in the contraction and relaxation of GI smooth muscle. q The submucosal plexus is involved with secretory and absorptive functions of the GI epithelium, local blood flow, and neuroimmune activities. q Neurotransmitters of ENS: ACh, ATP, Substance P, 5-HT.
  • 13. Difference between Sympathetic and Parasympathetic Nervous System
  • 14. q Autonomic nervous system supply all innervated structures of the body except skeletal muscle, which is served by somatic nerves. q The most autonomic ganglia that are entirely outside the cerebrospinal axis. Somatic nerves contain no peripheral ganglia, and the synapses are located entirely within the cerebrospinal axis. q Many autonomic nerves form extensive peripheral plexuses; such networks are absent from the somatic system. q Postganglionic autonomic nerves generally are nonmyelinated; motor nerves to skeletal muscles are myelinated. q When the spinal efferent nerves are interrupted, smooth muscles and glands generally retain some level of spontaneous activity, whereas the denervated skeletal muscles are paralyzed. Difference between Autonomic and Somatic Nervous System
  • 15. Neurochemical transmission: Steps Involved in Neurotransmission: 1. Axonal Conduction 2. Junctional Transmission i. Storage and release of transmitter ii. Interaction of the transmitter with postjunctional receptors and production of the postjunctional potential iii. Initiation of postjunctional activity iv. Destruction or dissipation of the transmitter v. Nonelectrogenic functions
  • 18. q Conduction refers to the passage of an electrical impulse along an axon or muscle fiber. q At rest, the interior of the typical mammalian axon is about 70 mV negative to the exterior. q In response to depolarization to a threshold level, an action potential (AP) is initiated at a local region of the membrane. q The AP consists of two phases. Following depolarization that induces an open conformation of the channel, the initial phase is caused by a rapid increase in the permeability and inward movement of Na+ through voltage- sensitive Na+ channels, and a rapid depolarization from the resting potential continues to a positive overshoot. q The second phase results from the rapid inactivation of the Na+ channel and the delayed opening of a K+ channel, which permits outward movement of K+ to terminate the depolarization. q Although not important in axonal conduction, Ca2+ channels in other tissues (e.g., L-type Ca2+ channels in heart) contribute to the AP by prolonging depolarization by an inward movement of Ca2+. q This influx of Ca2+ also serves as a stimulus to initiate intracellular events, and Ca2+ influx is important in excitation-exocytosis coupling (transmitter release). q The transmembrane ionic currents produce local circuit currents such that adjacent resting channels in the axon are activated, and excitation of an adjacent portion of the axonal membrane occurs, leading to propagation of the AP without decrement along the axon. 1. Axonal Conduction
  • 19. 2. Junctional Transmission Goodman and Gillman Book _The Pharmacological Basis of Therapeutics_13th Edition, 2017
  • 20. q Transmission refers to the passage of an impulse across a synaptic or neuroeffector junction. q The arrival of the action potential at the axonal terminals initiates a series of events that trigger transmission of an excitatory or inhibitory biochemical message across the synapse or neuroeffector junction. i. Storage and release of transmitter: § The nonpeptide (small-molecule) neurotransmitters, such as biogenic amines, are largely synthesized in the region of the axonal terminals and stored there in synaptic vesicles. § Neurotransmitter transport into storage vesicles is driven by an electrochemical gradient generated by the vesicular proton pump (vesicular ATPase). § Synaptic vesicles cluster in discrete areas underlying the presynaptic plasma membrane, termed active zones, often aligning with the tips of postsynaptic folds. Proteins in the vesicular membrane (e.g., synapsin, synaptophysin, synaptogyrin) are involved in development and trafficking of the storage vesicle to the active zone. § The processes of priming, docking, fusion, and exocytosis involve the interactions of proteins in the vesicular and plasma membranes and the rapid entry of extracellular Ca2+ and its binding to synaptotagmins. 2. Junctional Transmission
  • 21. Molecular basis of exocytosis: Docking and fusion of synaptic vesicles with neuronal membranes: 1. Vesicular docking in the active zone: Munc18 binds to syntaxin 1, stabilizing the neuronal membrane SNARE proteins. 2. Priming I: Syntaxin assembles with SNAP25, allowing for the vesicle SNARE protein synaptobrevin to bind to the complex. 3. Priming II: Complexin binds to the SNARE complex and allows for the vesicular synaptotagmin to bind Ca2+ that drives the full fusion process. 4. Fusion pore opening: Synaptotagmin interacts with the SNARE complex and binds Ca2+, permitting pore fusion and exocytosis of neurotransmitter. 5. Return to ground state: After fusion, the chaperone ATPase NSF and its SNAP adapters catalyze dissociation of the SNARE-complex 2. Junctional Transmission
  • 22. ii. Interaction of the transmitter with postjunctional receptors and production of the postjunctional potential: § The transmitter diffuses across the synaptic or junctional cleft and combines with specialized receptors on the postjunctional membrane; this often results in a localized increase in the ionic permeability, or conductance, of the membrane. § One of three types of permeability change can occur: -Generalized increase in the permeability to cations (notably Na+ but occasionally Ca2+), resulting in a localized depolarization of the membrane, that is, an EPSP. -Selective increase in permeability to anions, usually Cl–, resulting in stabilization or actual hyperpolarization of the membrane, which constitutes an IPSP. -Increased permeability to K+. Because the K+ gradient is directed out of the cell, hyperpolarization and stabilization of the membrane potential occur (an IPSP). 2. Junctional Transmission
  • 23. iii. Initiation of postjunctional activity: § If an EPSP exceeds a certain threshold value, it initiates a propagated action potential in a postsynaptic neuron or a muscle action potential in skeletal or cardiac muscle by activating voltage-sensitive channels in the immediate vicinity. § An IPSP, which is found in neurons and smooth muscle but not in skeletal muscle, will tend to oppose excitatory potentials simultaneously initiated by other neuronal sources. § Whether a propagated impulse or other response ensues depends on the summation of all the potentials. 2. Junctional Transmission
  • 24. iv. Destruction or dissipation of the transmitter: § When impulses can be transmitted across junctions at frequencies up to several hundred per second, there must be an efficient means of disposing of the transmitter following each impulse. § At cholinergic synapses involved in rapid neurotransmission, high and localized concentrations of Acetylcholinesterase (AChE) are available for this purpose. When AChE activity is inhibited, removal of the transmitter is accomplished principally by diffusion. § Rapid termination of Norepinephrine (NE) occurs by a combination of simple diffusion and reuptake by the axonal terminals of most of the released NE. § Termination of the action of amino acid transmitters results from their active transport into neurons and surrounding glia. § Peptide neurotransmitters are hydrolyzed by various peptidases and dissipated by diffusion. 2. Junctional Transmission
  • 25. v. Nonelectrogenic functions: The activity and turnover of enzymes involved in the synthesis and inactivation of neurotransmitters, the density of presynaptic and postsynaptic receptors, and other characteristics of synapses are controlled by trophic actions of neurotransmitters or other trophic factors released by the neuron or target cells. 2. Junctional Transmission
  • 26. Rang and Dale’s Pharmacology Book, 9th Edition,2019