Yerevan State Medical University after Mkhitar Heratsi M.G. Balasanyan, L.G. Dheryan, A.V. Baykov, A.G. Tananyan, N.A. Voskanyan Pharmacology Guideline For the third year students Pharmacology of autonomic nervous system Yerevan-2017-2018 Pharmacology of autonomic nervous system Nervous system is divided into 2 parts: Central nervous system (CNS) and peripheral nervous system (PNS). CNS in its` term consists of brain and spinal cord. PNS consists of all afferent (sensory) neurons, which provide impulse conduction from peripheral organs and all efferent (motor) neurons, which provide impulse conduction from center to periphery. Efferent part of nervous system includes 2 main parts: autonomic nervous system and somatic nervous system. Vegetative or autonomic nervous system acts out of human’s will and isn`t directly regulated by the human`s conscious. VNS maintains body homeostasis and regulates function of inner organs (digestion, blood supply of organs, regulation of blood pressure etc.). Synapses of SNS are localized in CNS, but peripheral synapses of VNS are localized out of CNS in ganglions. Preganglionic nerves of VNS are myelinated, postganglionic nerves are not myelinated. VNS innervates smooth muscles, myocardium and exocrine glands. Besides VNS is included also peripheral ganglions. The mediators of VNS are NA and ACH. Somatic nervous system (SNS) is regulated by conscious and regulates motor activity, breathing, position. SNS innervates skeletal muscles, synapses are located in CNS, nerve fibers are myelinated. SNS doesn`t have ganglions, the mediator of efferent ways is ACH (picture and table 1). 3 Picture 1. General description of somatic and autonomic nervous system Table 1: comparative properties of SNS and VNS Somatic Vegetative 1 Innervated organs Skeletal muscles All other organs 2 Localization of peripheral Mainly inside of Out of CNS /in synapses CNS ganglions/ 3 Neurons Myelinated Preganglionic are mielinated, postganglionic are non- mielinated 4 Existance of peripheral absent Exists ganglions 5 Efferent neurotransmitter acetylcholine Acetylcholine Noradrenaline According to neurotransmitter which is released from synapses VNS is divided into sympathetic /mediator is noradrenaline/ and parasympathetic nervous systems /mediator is acetylcholine/: These 2 systems have afferent, central and efferent parts. Afferent way of VNS. The majority of nerves are mixed and include nonmyelinated afferent nerve fibers. Their neurons are located in 4 ganglions of dorsal roots of spinal nerves and in sensory ganglions of cerebral nerves. These ways are conducting pain, cardio-vascular, respiratory and other inner reflexes. VNS Central centers. Are located in hypothalamus. Their dorsal and lateral nuclei are symphatic, anterior and intermediate are parasymphatic. Parasymphatic central neurons have cranio-sacral location. Picture 2. The general description of location of sympathetic and parasympathetic nervous systems: Efferent way of VNS Majority of organs receive both sympathetic and parasympathetic innervations, which are functionally controversial. Some inner organs receive only sympathetic or parasympathetic innervations. For example, majority of blood vessels, spleen, sweat glands and piloerectile muscles receive mainly sympathetic innervations, but cilliary muscle, glands system of stomach and pancreas receive mainly parasympathetic innervations. 5 Efferent way of VNS consists of two neurons: preganglionic and postganglionic. Bodies of preganglionic neurons of parasympathetic nervous system have craniosacral localization. Craniosacral nuclei are localized in midbrain and medulla. In this case cholinergic neuronal endings are going through the following craniocerebral neurons: lll /n.oculomotorius/, Vll /n.facialis/, lX /n. glossopharyngeus/, X /n.vagus/. Bodies of preganglionic neurons in sacral part of spinal cord are localized in lateral horns of grey substance (picture 2). Bodies of preganglionic nerves of sympathetic nervous system are localized mainly in thoracolumbal part of spinal cord in lateral horns: C8, Th1–L3. Preganglionic axons of both sympathetic and parasympathetic neurons are interrupted in vegetative ganglia, where with ganglionar neurons they form synaptic contact. Postganglionic neurons are started from these ganglions, which innervate the organ. Sympathetic preganglionic nerves are short and their ganglions are localized far from organ in paravertebral column. Postganglionic nerves are longer (Picture 2). Parasympathetic preganglionic nerves are longer and most of them are interrupted in ganglions which are localized near organs or inside of organs. Parasympathetic postganglionar nerves are short. Mediator in all vegetative ganglions is acetylcholine, so both sympathetic and parasympathetic preganglionic nerves are cholinergic, but sympathetic postganglionic nerves are adrenergic, parasympathetic postganglionic nerves are cholinergic. 6 As it was mentioned above, efferent way of VNS consists of 2 neurons. There are some exceptions, for instance, efferent neurons which innervate adrenal medulla. The chromaphinic cells of adrenal medulla are close to neurons of sympathetic ganglions, so only preganglionic /cholinergic/ neurons are involved in innervation of adrenal medulla, where mediator is acetylcholine. So, here we have only one way, which consists of one neuron only and stimulation of this neurons causes release of adrenaline (Table 2). Thus, motor, vegetative preganglionar and parasympathetic postganglionar nerves are cholinergic, but sympathetic postganglionar nerves are adrenergic. Table 2. Comparative properties of Parasympathetic /PNS/ and Sympathetic /SNS/ nervous systems SNS PNS 1 Central part thoracolumbal craniosacral /Th1-L2 or L3/ part /involved in III, of spinal cord VII, IX, X, S2-S4 neurons/ 2 Localization of ganglions Out of organs Near organs or inside of organs 3 Length of postganglionar long Short neurons 4 Neurotransmitter Noradrenaline Acetylcholine /mediator/ acetylcholine 5 Main function Mobilization of Accumulation of strength and energy, digestion defense of organism in stress and emergency situation 7 Intestinal neuronal system /INS/ complex of different neurons, which is localized in walls of GIT. Some authors consider INS as the third part of VNS. It consists of muscular plexus /Auerbach plexus/, submucous plexus /Plexus of Mejsnier/ and sensitive – endings of afferent neurons. This system receives preganglionic neurons from PNS and postganglionic axons of SNS. Neurons which begin from this plexus reach the mucous membrane of intestines and regulate motor activity of intestines and secretor activity of cells. INS of VNS has only modulating activity, because here there are a lot of neuromediators and neuroregulating substances: NO, neuropeptides, substance P, serotonine etc.) Structure of synapse of autonomic nervous system Synapse consists of 1. Presynaptic membrane, from where, in response to impulse /action potential/, is taking place release of mediator, which is synthesized in axonal endings and is accumulated in vesicles. 2. Postsynaptic membrane, where mediator is recognized and the appropriate response is formed. 3. Synaptic cleft, which is the space of 20-40nm between presynaptic and postsynaptic membranes. It is polysaccharidal jelly with many tubules where mediator is diffused. 4. Connetive tissue filaments, which limits synapses and prevent diffusion of mediator to systemic blood flow (picture 3). 8 Picture 3. Structure of synapse Main stages of neurotransmission 1. Synthesis and accumulation of mediator 2. Impulse transmission and release of mediator 3. Interaction of mediator with pre- and postsynaptic membrane receptors 4. Formation of postsynaptic activity 5. Mediator effect elimination 1. Synthesis and accumulation of mediator Synthesis of non-peptide mediators takes place in axonal endings and synthetized mediator is accumulated in special synaptic vesicles. Mediators with peptide properties are synthesized in neuronal bodies then go to the axonal endings are accumulated in vesicles, where they are 9 transformed into main mediators. Transport of mediators or premediators into vesicles are perfomed by means of proton pump. At rest only small quantity of mediator is released into synaptic cleft and they form tiny postsynaptic potential /0,1-3mV/. This process provides physiological reactivity of effector organ. Synaptic vesicles are localized and accumulated near presynaptic membrane in special part which is called «active zone» (picture 4). 2. Impulse transmission and release of mediator. Permeability of axonal membrane for K+ and H+ ions at rest is very high, and the quantity of K+ and H+ ions inside of cell is very high, but in outside of cell Na+ and Cl- are in large quantity. As a result the inner surface of cell membrane has negative charge compare to upper surface of membrane. Depolarization of axonal ending brings to opening of potential dependent Na+–channels and influx of Na+-ions which cause change of charge. This is the first stage of depolarization. On the second stage of depolarization inactivation of potential dependent Na+–channels and opening of K+-channels takes place which brings to limitation of depolarization and repolarization of presynaptic membrane. Ionic ratio comes back to initial level in refractory period due to activity of Na+ / K+ – ATPase. Increase of level of Na+ and mainly Ca2+-ions in presynaptic part result in interaction between proteins of synaptic vesicles /synaptotagmine, synaptobrevin /VAMP-vesicle-associated