The Autonomic Nervous System 1. Anatomy and general organisation

Transcription

1 The Autonomic Nervous System 1. Anatomy and general organisation Carlo Capelli, MD Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Italy

2 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

3 Hystoric Remarks The autonomic nervous system was described at the beginning of the twentieth century by Langley and coworkers an the term Autonomic Nervous System was first used by Langley in 1921 As defined, ANS is a motor system The ANS consists of nerve cells and nerve fibres, by means of which efferent impulses pass to tissues other than striated muscles

4 Functions ANS is responsible for controlling our internal environment through autonomic processes (metabolic, cardiopulmonary, hormonal, visceral) that never stop and continue independently of our awakeness This is in contrast with those parts and functions of our CNS involved, f.i., in voluntary movements, voluntary cognitive processes

5 General Organisation 1. Somatic motor neurons (soma located in CNS, excitatory, monosynaptic link with the target, i.e striated muscle) 2. Autonomic motor neurons: innervate organs, blood vessel, adipose tissue, components of the skin and also organs of the immune system ANS has three Divisions 1. Sympathetic 2. Parasympathetic They can function independently, but they often work sinergistically 3. Enteric (located within the wall of gastrointestinal tract; a network - plexus - of afferent neurons, interneurons an motor neurons) that can function independently from other parts of ANS

6 Sympathetic and Parasympatehic Divisions General organization Two-synapse pathways Cell bodies in the CNS: preganglionic neurons Outside CNS they make synapses with postganglionic neurons in peripheral ganglia Axons from postganglionic neurons project to target organs

7 Sympathetic Division-Preganglionic Neurons Thoracolumbar Division Preganglionic Neurons Soma in the thoracic and upper lumbar spinal cord between T1 and L3 They lie in the so called intermediolateral cell column (lateral horn) Axons exit the spinal cord through the ventral roots along with the somatic motor neurons. After entering the spinal nerves, they enter the white rami (myelinated)communicantes and enter the nearest paravertebral ganglion

8 Sympathetic Division-Paravertebral ganglia 1 Paravertebral Ganglia The chain extends from the neck to the coccyx Superior cervical ganglion (C1 - C4): head, neck Middle (C5, C6) and Inferior (C7,C8) fused with the first thoracic to form Stellate ganglion, which, together with upper thoracic and middle cervical, innervates, heart, lungs and bronchi 3 2

9 Sympathetic Division-Prevertebral ganglia Prevertebral Ganglia They form the prevertebral plexus This organisation is possible as a preganlgionic fiber synapses on many postganglionic neurons located within one or several nearby ganglia

10 Sympathetic Division-Postganglionic Neurons Postganglionic neurons Axons from paravertebral ganglia via the gray (unmyelinated) rami communicantes (from C2 to coccyx) Postganglionic neurons of prevertebral ganglia: axons travel within other nerves or along blood vessels They are rather long

11 Parasympathetic Division-Pre/Postganglionic Neurons Preganglionic Neurons Soma of preganglionic neurons: medulla, pons and midbrain and S2-S4 level of spinal cord Craniosacral Division Preganglionic fibers of the brain stem: they distribute with four cranial nerves (III, VII, IX, X) Preganglionic fibers S2-S4: pelvic splachnic nerves to terminal ganglia of descending colon, rectum, bladder Postganglionic Neurons Located at the periphery and widely distributed within the walls of their target organs Postganlgionic fibers are short

12 Parasympathetic Division - III, VII, IX and X Cranial Nerves III: Edinger-Westphal Nucleus Preganglionic fibers via the Oculomotor Nerve They synapse in the Ciliary Ganglion Postganglionic fibers: papillary constrictor smooth muscle, smooth muscle of the ciliary body

13 Parasympathetic Division - III, VII, IX and X Cranial Nerves VII: Superior Salivatory Nucleus Preganglionic fibers via the Facial Nerve They synapse: 1. in the Pterygopalatin Ganglion Postganglionic fibers: lacrimal glands 2. In the Submandibular Ganglion Postganglionic fibers: submandibular and sublingual glands

14 Parasympathetic Division - III, VII, IX and X Cranial Nerves X: Dorsal Motor Nucleus Vagi (DMN), Nucleus Ambiguus (NA) and IX Preganglionic fibers via the Vagus Nerve (viscera of thorax and abdomen between pharynx and distal colon) They synapse in the esophageal, pulmonary, cardiac plexuses with ganglia located within the target organs DMN: gastric, insulin, glucagon secretions NA: striated muscle of pharynx, larynx, esophagus, bradycardia

15 Convergence and Divergence Convergence: Many preganglionic axons may synapse on a single postganglionic neurons (4-15 pre to one post) A single synaptic event is not sufficient to initiate an action potential in the postganglionic neurons, but the summation of multiple events is required to initiate it Divergence: relatively few preganglionic neurons synapse with many postganglionic neurons located within one or several nearby ganglia (1:10; 1:100) It allows for massive activation by few spinal centers of multiple sympathetic targets under extreme conditions (flight or fight) However, any impulse crosses a single synapse between pre and postganglianic neurons

16 General concepts Synaptic physiology of ANS Many visceral targets receive both inhibitory and excitatory synapses These antagonistic synapses arise form the two divisions of ANS 1. organs activated during exercise: a. sympathetic: excitatory b. parasympathetic: inhibitory 2. organs whose activity increases at rest a. parasympathetic: excitatory b. sympathetic: inhibitory Exception: sweat glands, piloeroector muscles and most peripheral blood vessels receive only sympathetic inputs

17 Synapses of ANS Synaptic physiology of ANS Rather than synaptic terminals, many postganglionic autonomic neurons have varicosities distributed along their axons within the target organs Many varicosities form en passant synapses with the target cells Synapses of ANS with the target system shown in scanning electron micrograph

18 Preganglionic synapses Ganglionic Transmission Synaptic transmission between pre- and post-ganglionic neurons is mediated by acetylcholine acting on nicotinic ionotropic receptor N 2 They are different from those found at neuromuscular junction (N 1 ) Pharmacology of receptors N 2 stimulated by tetramethylammonium resistent to D-tubocurarine N 1 stimulated by decamethonium blocked by D-tubocurarine

19 Parasympathetic Postganglionic synapses Postanglionic Transmission Synaptic transmission between post-ganglionic neurons and target organs is mediated by acetylcholine acting on muscarinic metabotropic receptor M Activation can either stimulate or inhibit the function of the target cell

20 Physiology Muscarinic receptors They are metabotropic receptors that interact with heterotrimetric G proteins Their actions are mediated by second messengers and are slow and prolonged The interactions occur by 1. Stimulating the hydrolysis of phosphoinositide (PIP 2 ) and increase [CA ++ ] and activate protein kinase C 2. Inhibiting adenylate cyclase and decreasing the levels of camp 3. Directly modulating K + channels via the G-protein βγ complex Pharmacology Five different subtypes (M 1 to M 5 ) coded by five different genes They are stimulated by Ach and blocked by atropine M 1, M 3, M 5 : via the hydrolisis of PIP 2 M 2, M 4 : inhibition of adenylate cyclase and decrease the levels of camp The five subtypes are heterogeneously distributed among tissues, they are found both pre and postsynaptically, many smooth muscles coexpress multiple muscarinic receptors

21 Sympathetic Postganglionic synapses Postanglionic Transmission Synapses are noradrenergic (noradenaline, NA) A noticeable exception: sweat glands, ACh α and β metabotropic receptors G-protein coupled Each class has multiple subtypes: α 1, α 2, β 1, β 2 and β 3 α: greater affinity fo NA β: greater affinity for A Receptors have tissue-specific distribution: α 1 blood vessels α 2, presynaptic β 1, heart β 2,bronchial muscle, lungs β 3,adipose tissue

22 Sympathetic Postganglionic Synapses Adrenal medulla: is a special adaptation of this division of ANS homologous to a sympathetic ganglion the postsynaptic targets are the chromaffin cells innervated by pregangliar sympatehtic neurons (nicotinic Ach receptors) chomaffin cells release epinephrine or adrenaline, A in the blood stream causing generalized effects Postanglionic Transmission Synapses are noradrenergic (noradenaline, NA) A noticeable exception: sweat glands, ACh α and β metabotropic receptors G-protein coupled Each class has multiple subtypes: α 1, α 2, β 1, β 2 and β 3 α: greater affinity fo NA β: greater affinity for A Receptors have tissue-specific distribution: α 1 blood vessels α 2, presynaptic β 1, heart β 2,bronchial muscle, lungs β 3,adipose tissue

23 Pharmacology α 1 agonists: Sympathetic Postganglionic Synapses phenylephrine, methoxamine α 1 antagonists: phentolamine prazosin (selective), α 2 agonists: α 2 antagonists: β 1 agonists: β 1 antagonists: β 2 agonists: β 2 antagonists: β 3 agonists: β 3 antagonists: clonidine (reduces the NA release due to presynaptin hinibition, bradycardia, hypotension) yohimbine isoproterenol, dobutamine (heart failure) metoprolol, atenolol (beta blockers) (hypertension) terbutaline, isoproterenol, salbutamol, formoterol (asthma) butoxamine, propanolol, (beta blockers) amibegron, solabegron, isoproterenol SR 59230A

24 Receptor Distribution - A sinopsys Target organs Cholynergic effectc Receptors Adrenergic effects Eye Pupillar radial m. Pupillar constrictor m. Cyliary m. Heat NSA Atria AVN, ventricular condiction system Myosis Contraction for close vision 2 Badycardia Decrease of contractility and velocity of conduction Decrease of velocity of conduction Slight decrease of contractility Mydriasis Relaxation for remote vision Tachycardia Increase of contractility Increase of velocity of conduction Blood vessels Coronaries Skin Sletal muscle CNS Lungs NS NS NS NS NS Increase of contractility Increase of velocity of conduction Increase of automaticity and frequency of hydiopathic pacemakers Constriction Dilatation Constriction Constriction Dilatation Constriction Constriction Dilatation Splanchnic Salivare glands NS NS 2 Constriction Dilatation Constriction

25 Receptor Distribution - A sinospys Target organs Cholynergic effects Receptprs Aderenergic effects Kidney Proximal tubuli Renine release NN 2 Increased reabsorbtion of natrium Increased release of renine Lung Bronchial smooth muscles Bronchial glands Stomach Motility and tone Sphincters Secretion Contraction Dilatation Increase Relaxation Stimulation 2 Relaxation Uncertain 2, 2 Decrease (normally) Contraction (normally) Inhibition (?) GI Motility and tone Sphincters Secretion Increase Relaxation Stimulation 2, 2 Decrease (normally) Contraction (normally) Inhibition (?) Gallbladder and ducts Contraction Relaxation Urinary bladder Detrusor urinae Sphincter, trigone Urether Motility and tone Sphincter, trigone Utero Contraction Relaxation Uncertain Variable Relaxation 2 2 Relaxation (normally) Contraction Increase Pregnancy: contraction No pregnancy: relaxation

26 Signaling Pathways for Nicotinic, Muscarinic and Adrenergic Receptors (Synopsis) RECEPTOR TYPE AGONISTS ANTAGONISTS G PROTEIN N 1 nicotinic, ACh N 2 nicotinic, ACh M 1 /M 3 /M 5 muscarinic, ACh ACh, (nicotine decamethonium) ACh, (nicotine, TMA) ACH (muscarine) D-Tubocurarine. α- bungarotoxin Hexamethonium Atropine, pirenzepine (M 1 ) M 2 /M 4 muscarinic, ACh ACH (muscarine) Atropine, methoctramine (M 2 ) α 1 -adrenergic NA>A (phenilephrine) LINKED ENZYME 2ND MESSENGER Gα q PLC IP 3 and DAG Gα i and Gα o Adenylyl ciclase [camp] i Phentolamine Gα q PLC IP 3 and DAG α 2 -adrenergic NA>A (clonidine) Yohimbine Gα i Adenylyl ciclase β 1 -adrenergic β 2 -adrenergic β 3 -adrenergic A>NA (dobutamine, isproterenol) A>NA (terbutaline, isoproterenol) A>NA (isoproterenol) Metoprolol Gα s Adenylyl ciclase Butoxamine Gα s Adenylyl ciclase SR 59230A Gα s Adenylyl ciclase [camp] i [camp] i [camp] i [camp] i ACh: acetylcholine; camp, cyclic adenosine monophosphate; DAG, diacylglicerol; A, adrenaline; NA, noradrenaline; IP3, inositol 1,4,5-triphosphate; PLC, phospholipase C,;TMA, tetramethylammonium

27 Bibliography Boron WF, Boulpaep EL, Medical Physiology, Saunders Fisiologia dell Uomo, autori vari, Edi.Ermes, Milano Capitolo 4: Il Sistema nervoso vegetativo