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The Autonomic Nervous System 2. Physiology • • Carlo Capelli, MD Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Italy The Autonomic Nervous System Goals - General organization - Specific organization: sympathetic and parasympathetic divisions, ENS - Synaptic physiology and pharmacology: Preganglionic synapses (nicotinic receptors) Parasympathetic Postganglionic synapses (muscarinic receptors) Sympathetic Postganglionic synapses (noradrenergic receptors) - Divergence and Convergence - Functions of ANS: closed feedback control loop and control in ANS Integrated function • Sympathetic anc Parasympathetic divisions act sinergistically on several organs and/or systems • A good example of this behaviour is the integrated action on the cardiovascular system Sympathetic and Parasympathetic Effects in the Cardiovascular System Sympathetic input to the heart • Cardiac nerves form a plexus that innervates atria, SA node, ventricula • Effects: tachicardia (right cardiac nerve) and increase of contractility (left cardiac nerve) • β1 receptors Parasympathetic input to the heart • Right vagus (inhibit SA node) and left vagus (inhibit conduction of AV node), myocardial tissue • Effects: bradycardia, decrease AV conduction speed, less contractility Sympathetic input to the blood vessel • Vasocostriction or vasodilatation: • Which agonist is released ? • Which adrenoreceptor that agonist bindes to ? • Receptor occupancy causes vasoconstriction or vasodilation ? • Which type of receptor subtypes is present or prevail on the target organ ? Sympathetic and Parasympathetic Effects in the Cardiovascular System Sympathetic input to the blood vessel • NA has greater activity on and binds with greater affinity to α receptor • A has greatest activity on and binds with greater affinity to β receptor • However, NA can also activate β receptor: β1 has about the same affinity for NA and A; β2 has a higher affinity for A than for NA • However, A can also activate α receptor • Vasoconstriction is an α1 effect • Vasodilation is a β2 effect • Many blood vessels are populated with a mixture of α and β receptor subtypes. The response depends on the relative dominance of one of the subtypes • Therefore, the ultimate outcome in the target tissue depends on the heterogeneous mixutures of agonists and of types of receptors • Example: - blood vessel of the skin have only α1: only vasocostriction - coronary blood vessels: β2 > α: dilatation prevails. Sympathetic and Parasympathetic Effects in the Cardiovascular System Paraympathetic input to the blood vessel • Parasympathetic vasodilator fibers (releasing ACh) are far less common than vasoconstrictor sympathetic fibers • They supply salivary glands, some GI glands and erectile tissue • They indirectly cause vasodilation binding to M receptor on neighboring cells • ACh binds to M2 receptors of postgnalgionic sympathetic neurons decreasing [cAMP] and inhibiting the release of NA • in erectile tissue ACh binds to M3 receptors on entothelial cells, IP3 is released and [Ca++] increases stimulating nitric oxyde synthase to produce NO, wich diffuses to the smooth muscel cells, activates soluble guanyl ciclase with cGMP production and activation of protein kinase G. The subseqent phosphorilation of MLCK causes relaxation. • in salivary glands ACh stimulates the production of callicreine that clivates kininogenes to vasodialting kinines (bradykinin) ANS and Control Systems • ANS monitors, controls and maintains within an optimal range several physiological paramaters by means of a series of properly damped feedback control loops Error signal Setpoint + E (s) - G (s) H (s) Y (s) CNS resetting mechanisms Output H (s) Y (s) Perturbations Feedback • The internal environment has to be monitored (feedback) and compared to some set point (SP) and an output produced to reduce the error signal (ER) Afferent Limb of Visceral Control System • Viscera are also innervated by afferent fibers that monitor nociceptive mechanical (stretch, arterial pressure, bladder distension), thermal and physiological chemical (PO2, PCO2, pH, glucose) or noxious chemical stimuli • Many of these unmyelinated fibers travel in sympathetic nerves, most with parasympathetic fibers • Their cell bodies are located in the dorsal root ganglia • The largest concentration of VA is found in the vagus nerve that carries non-nociceptive mechanical and chemical afferent input from all the viscera (gastric distension) of thorax and abdomen • Cell bodies of these afferents are located in the nodose ganglion Afferent Limb of Visceral Control System • Some of these afferents origin from specialised receptors (baroreceptors, chemoreceptors); others can monitor local chemical (glucose, pH, K+), thermal (cold, heat) local and/or blood conditions • Other afferents encode exteroceptive informations that can initiate an autonomic response Baroreceptors Autonomic Reflexes and Anticipatory Behaviour 1. Feedback loop mechanism Arterial pressure control • Afferent fibers (IX and X cranial nerves) respond to elevation of AP with increased activity as a result of activation of baroreceptors and carry these informations to brainstem • The level of AP is compared to a reference Brain AP value (SP) Stem • reciprocal actions in the brainstem are initiated in proportion to ER= AP- SP i) inhibition of sympathetic Autonomic cardioacceleratory and vasocostrictive Output nerves ii) excitation of parasympathetic vagus nerve • HR is slowed, the arterioles vasodilate and AP is lowered • The behaviour of this system can be modified by resettin the SP value by CNS (PS) (S - A Node) Autonomic Reflexes and Anticipatory Behaviour 1. Anticipatory Mechanisms • ANS system also anticipates the future needs of behaviour of the individuals • F.I., efferents from motor or premotor cortical areas are irradiated at the early beginning of (or even before) exercise and activate cardiovascular and respiratory control areas in the brainstem: Central Command • Because of this anticipatory, feedforward stimulation, HR and V’A can promptly increase at the beginning of exercise and AP set point is reset Brainstem Nuclei and Forebrain Structures involved in ANS functions “ …the word autonomic suggest a much greater degree of independence of the central nervous system than in fact exists” • Indeed, it was soon realised that ANS is under the control of centers in the brain 1. A variety of brainstem structures/nuclei are involved in visceral control. - Nucles Tractus Solitarius (NTS), ventrolaterla medulla, medullary raphe, reticular formation, locus coerules, parabrachial nucleus, nuclei of the cranial nerves - They may play a well-defined role or they are linked to multiple autonomic functions Brainstem Nuclei - NTS • • • NTS is one of the most important strucure, located in the medulla It integrates multiple inputs from visceral afferents and exerts control over autonomic output it is the major lower brainstem command center for visceral control • It contains second-order sensory neurons and receives baroreceptors, chemoreceptor and visceral non-nociceptive afferents (tractus solitarius) from organs of thorax and abdomen • Subnuclei devoted to cardiovascualr, respiratory, gustatory and GI input and control • Outputs to several parts of CNS (SC) • NTS CONNECTIONS TO/FROM NTS Receive inputs from Vagus n. (peripheral chemoreceptors/aortic bodies, baroreceptors, nonnociceptive afferent input from every organ of thorax and abdomen Connections of NTS Glossopharyngeal N. (taste and peripheral chemoreceptors/carotid bodies,carotid baroreceptors) Facial n. (taste) Trigeminal n. (teeth, sinuxes) Ventrolateral medulla Medullary raphe Area postrema Periacqueductal gray Prabrachial nucleus Hypothalamus Cerebral cortex Send Outputs to Intermediolateral cell column, sacral parasympathetic neurons Preganglionic sympathetic neurons Dorsal motor nucleus of vagus Preganglionic parasympathetic neurons Nucles ambiguus Ventrolateral medulla Medullary raphe Area postrema Prabrachial nuclei Reticular formation Forebrain nuclei Phrenic motor nucles and other respiratory output pathways Hypothalamus Forebrain Several regions of the forebrain play a role in coordinating and modulating the activities of the lower centers of ANS Hypothalamus: paraventicular nucleus it projects to parabrabrachial nucleus, medullary raphe, NTS, central grey matter, ILC of spinal cord it coordinates autonomyc function with feeding,thermoregulation, circadian rythms, water balance,emotions, sexual drive, reproduction Limbic system: includes the majority of the forebrain regions involved in this modulation Neocortex: Minimal conscious control of ANS, but emotions, mood, anxiety, stress and fear cal alter ANS functions and responses Afferent limb and Referred Pain • In the CNS (spinal cord and brain stem) the visceral pain is mapped viscerotopically • The visceral afferents terminate in laminae I and V of the dorsal horn of spinal cord • In spinal cord there is a large class of cells that respond both to visceral and somatic afferent stimulation, i.e. thare is a substantial divergence in the afferent input • The nociceptive fibers travel with sympathetic fibers and enter the spinal cord at a specific segmental level • Viscerotopic mapping is lost at the level of the cerebral cortex • Thus, awareness of visceral pain is not localized to a specific organ,but it is referred to the dermatome (delimited kjin area) innervated by the same spinal nerve. • This is called referred pain. More complications: Nicotinic and Muscarinic Receptors on Postganglionic Neurons • Some sympathetic and parasympathetic postganglionic neurons have muscarinic in addition to nicotinic receptors • This means that the release of ACh from preganglionic neurons may induce both muscarinic and nicotinic effects • Multiphasic response: - fast EPSP, nicotinic - slow EPSP, muscarinic More complications: Nicotinic and Muscarinic Receptors on Postganglionic Neurons • Muscarinic neurotransmission inhibits specific K+ current, M current • At baseline M current is active, thereby producing a slight depolarization • Electrical stimulus of the neurons produces only a single spike • With muscarinic stimulation M current is turned off leading to a small depolarization • If stimulation is repated, repetitive spikes appear • Muscarinic receptors modulates the repetitive firing properties and enhance the ability of ANS to control visceral activity More complications: non Classic Neuromediators may be Released at Each Level of ANS • Some neurotransmissions in the ANS involves neither adrenergic nor cholinergicpathways • Many neuronal synapses use more that a single neurotransmitter - cotransmission • Several different neurotransmitter may be found within some neurons - colocolization • Non noradrenergic non cholinergic transimmiters may be found at every level of ANS, especially in the ENS • It is not clear what controls the release of each of the many neurotransmitters, but the proportions of released neurotransmitters are controlled by firing frequences. Neurotransmitters and Neuromodulators in the ENS NEUROTRANSMITTERS AND NEUROMODULATORS IN ENS Acetylcholine (Ach) Noradrenaline (NA) Serotonin (5-HT) Dopamine Tachykinines (substance P, neurokinin A, neuropetide K, neuropeptide γ) Nitric Oxide (NO) Adenosine triphosphate (ATP) Vasoactive intestinal polypeptide (VIP) γ-Aminobutyric acid (GABA) Chlecystokinin (CCK) Somatostatin Gastrin-releasing peptide (GRP) Enkephalines Dynorphin Calcitonin gene-related peptide (CGRP) Neurotensin Galanin Neurotransmitters Present Within the ANS NEUROTRANSMITTERS PRESENT WITHIN THE ANS SYNAPSE TRANSMITTERS Presynaptic Postsynaptic CNS neurons Preganglionic autonomic neurons Glutamate Glycine Substance P Serotonin Noradrenaline TRH Enkephalines Neuropeptide γ Neurotensin Neurophysin II Oxytocin Somatostatin Preganglionic autonomic neurons Postganglionic autonomic neurons Acetylcholine Substance P CGRP Postganglionic autonomic neurons Target cell Noradrenaline Acetylcholine NO Neuropeptide γ Galanin Somatostatin VIP Opioid peptides Visceral afferents Neurons in autonomic ganglia or spinal cord Substance P CGRP Interneurons Peripheral autonomic ganglia and ENS Dopamine Enkephalines Nonclassic Transmitter - ATP • Postganglionic sympathetic vasoconstrictor neurons • Purinoreceptors (P2x, ionotropic, P2γ, P2u, metabotropic) • Vasoconstriction • Cotransmission: ATP, NPY and NA • P2x receptors in smooth muscles have a relative high C++ permeability; rapid depolarisation and contraction followed by a second, slower phase Nonclassic Transmitter - NO NO (nitric oxide) • A short lived, vasodilating gas produced locally from L-Arginine by the enzyme nitrico oxide synthase (NOS) • Activated by shear stress on endothelial cells Nonclassic Transmitter - NO • NOS is found also in pre and postganglionic sympathetic and parasympathetic neurons • A parasympathetic neurons, f.i, may release at the same time (cotransmission) Ach, NO and VIP and potentiate smooth muscel relaxation. Enteric Nervous Sytem (ENS) • • • • A collection of nerve and sensory, motor and inter-neurons foming plexus that surround the GI tract Myenteric plexus: between external longitudinal and deeper circular smoothmuscle layers - motility controlo Submucosal plexus (Auerbach): between circular muscle and muscolaris mucosae- secretion control They receive: 1. Preganglionic parasympathetic fibers 2. Postganglionic sympathetic fibers Postganglionic Sympathetic Afferents Preganglionic Parasympathetic Auerbac Meissner Scanning electron micrograph Enteric Nervous Sytem (ENS) • ANS modulates the activity of ENS, but it can by and large function normally without extrinsic control SNC Sensory neurons Chemoreceptors Interneurons Motor neurons Reflex circuits Inhibitory Mechanoreceptors Chemoreceptors Epitelium Muscles Motor programs Excitatory Blood vessels Bibliography • Boron WF, Boulpaep EL, Medical Physiology, Saunders • Fisiologia dell’Uomo, autori vari, Edi.Ermes, Milano – Capitolo 4: Il Sistema nervoso vegetativo