Introduction to the Autonomic Nervous System

Autonomic Nervous System (ANS) Nervous system Central Nervous System Brain Spinal cord Peripheral Nervous System Motor (efferent) neurons Atomic Nervous System sympathetic nervous system Sensory (afferent) neurons Somatic Nervous System parasympathetic nervous system Just have a look The Autonomic nervous system is a set of pathways to and from the central nervous system (CNS) that innervates and regulates smooth muscle, cardiac muscle, and glands. Autonomic nervous system plays a major role in homeostasis. non-homeostatic organs such as the reproductive system. Autonomic nervous system output too many visceral organs is continuous (tonic). Unlike the somatic nervous system, who’s out-put to skeletal muscle is phasic and undergoes periods of repose. Autonomic nervous system activity changes in anticipation of demands. Phasic: activates and stops (so it needs time to relax) When the body needs a change for e.g; (if you need to digest food, the activity of GI System increases by the ANS) Autonomic nervous system output is coordinated with somatic activity to provide supportive visceral function. (e.g., blood flow) some of these activities are controlled almost entirely and some only partially by the autonomic nervous system. One of the most striking characteristics of the autonomic nervous system is the rapidity and intensity with which it can change visceral functions. For instance, within 3 to 5 seconds it can increase the heart rate to twice normal. has three divisions: Sympathetic Parasympathetic Enteric Just have a quick look Sympathetic nervous system has : CNS o intense ramification (divisions) (1:20). o very diffuse. o generalize action Catabolic in nature (expenditure in nature). o Sympathetic ganglia are located in the para-vertebral chain. o Pre-ganglionic neurons of the sympathetic nervous system Originate in spinal cord segments T1-L3, or the thoraco-lumbar region and they are Short and myelinated. o Post-ganglionic neurons of the sympathetic nervous system are long and un-myelinated. Postganglionic neurons of both divisions have their cell bodies in the autonomic ganglia and synapse on effector organs (e.g., heart, blood vessels, and sweat glands). Pre-ganglionic neurons have their cell bodies in the CNS and synapse in autonomic ganglia. Synapses between neurons are made in the autonomic ganglia. Effector organ Para-Sympathetic nervous system has : o o o o CNS Effector organ limited ramification (1:1) discrete (Separated) discharge affects specific effector system, individually anabolic in nature (conservation and restoration in nature) o Parasympathetic ganglia are located in or near the effector organs. o Pre-ganglionic neurons of the parasympathetic nervous system Originate in the nuclei of cranial nerves III, VII, IX, and X; and in spinal cord segments S2-S4, or the cranio-sacral region. About 75 percent of all parasympathetic nerve fibers are in the vagus nerves (cranial nerve X) and they are Long and myelinated. o Post-ganglionic neurons of the parasympathetic nervous system are short and unmyelinated Sympathetic fibers which do not synapse in the thoracic and upper lumber paravertebral ganglia of the sympathetic chain leave the ganglia and synapse with postganglionic neurons in other ganglia as followings: o Cervical ganglia: These receive extensions of the sympathetic trunk from T1 to T7. Their post-ganglionic fibers distribute themselves to structures in the head, neck and upper limbs. o Collateral ganglia (Coeliac and mesenteric): They are found in the abdomen and pelvis and their post-ganglionic fibers supply the abdominal viscera down to the proximal part of the colon. o Sacral ganglia: These receive a caudal extension of the sympathetic trunk from lower thoracic and upper lumber segments. Their post-ganglionic fibers are distributed to the distal colon, pelvic organs and lower limb. The adrenal medulla is essentially a sympathetic ganglion in which the post-ganglionic cells have lost their axons and secrete nor-epinephrine, epinephrine, and some dopamine directly into the blood-stream. The cholinergic pre-ganglionic neurons to these cells have consequently become the secreto-motor nerve supply of this gland. There is usually no acetylcholine in the circulation, and the effects of localized cholinergic discharge. Pre-ganglionic fibers synapse directly on chromaffin cells in the adrenal medulla. The chromaffin cells secrete epinephrine (80%) and nor-epinephrine (20%) into the blood and these two hormones in turn are carried in the blood to all tissues of the body. The circulating epinephrine and nor-epinephrine have almost the same effects on the different organs as the effects caused by direct sympathetic stimulation except: o The circulating epinephrine and nor-epinephrine effects last 5 to 10 times as long as sympathetic stimulation because both these hormones are removed from the blood slowly over period of 1 to 3 minutes. o The capability of epinephrine and nor-epinephrine to stimulate structure in the body that is not innervated by direct sympathetic fibers. The dual mechanism of sympathetic stimulation and circulating epinephrine and norepinephrine provides a safety factor, with one mechanism substituting for the other if it is missing. (so, if there is problem with one the other would try to take its place). Pheochromocytoma is a tumor of the adrenal medulla that secretes excessive amounts of catecholamine and is associated with increased excretion of 3-methoxy-4hydroxymandelic acid (VMA). In most situations, the sympathetic and parasympathetic act “synergistically” (they help each other). This functional synergy (cooperation) is particularly evident in reflex effects exerted on heart by baroreceptors. Excitation of the baro-receptors when the arterial blood pressure rises, decrease the heart rate and contractility of the heart; this is brought about by an increase in the activity of parasympathetic fibers to the heart, accompanied by decrease in sympathetic activity. In many organs receiving both sympathetic and parasympathetic innervation, There are also organs with only sympathetic or only parasympathetic innervation. The parasympathetic effect predominates under physiological conditions- these include the urinary bladder and some exocrine glands. Almost all blood vessels, spleen some exocrine glands and smooth musculature of hair follicles receive only sympathetic innervation. Adrenergic neurons release nor-epinephrine as the neurotransmitter. Cholinergic neurons, whether in the sympathetic or parasympathetic nervous system, release acetylcholine (ACh) as the neurotransmitter. Non-adrenergic, non-cholinergic neurons include some post-ganglionic parasympathetic neurons of the gastrointestinal tract, which release substance P, vaso-active intestinal peptide (VIP), or nitric oxide (NO). Based on the chemical mediator released, the autonomic nervous system can be divided into (cholinergic) and (nor-adrenergic) division. The neurons that are cholinergic are: o All pre-ganglionic neurons. o The anatomically parasympathetic post-ganglionic neurons. o The anatomically sympathetic post-ganglionic neurons which innervate sweat glands. o The anatomically sympathetic neurons which end on blood vessels in skeletal muscles and produce vaso-dilation when stimulated. ➢ The remaining post-ganglionic sympathetic neurons are nor-adrenergic 1.Adrenergic receptors (adreno-receptors) Classification of adreno-receptors: o Nor-adrenaline, the transmitter substance release by post-ganglionic sympathetic neurons and effector organ. o Adrenaline, a hormone secreted along with noradrenaline by adrenal medulla. o Dopamine, the metabolic precursor of nor-adrenaline and adrenaline, which functions as a neuro-transmitter in its own right in brain, and possible also in the periphery. o Isoprenaline, a synaptic derivative of nor-adrenaline that is not found in the body. Main pharmacological classification into α and β subtype, based originally on order of potency among agonist, later, selective antagonists. α Noradrenalin > adrenaline > isoprenaline β Isoprenaline > adrenaline > noradrenalin There are two main α-adrenao-receptors sub-type (α1: α1A, α1B, α1D and α2: α2A, α2B, α2C) and three β-adreno-receptors (β1, β2 and β3). α1 & β1 mostly produces excitation & α2 & β2 mostly produces inhibition. Dopamine (D1,D2,D3,D4 and D5) The basic adrenergic receptor structure is 7 trans-membrane domains (serpentine receptor) 1. ά1 Receptors which are located in: o vascular smooth muscle of the skin and splanchnic regions. o the gastrointestinal (GI). o bladder sphincters. o the radial muscle of the iris and. o Heart. Which produce: o excitation (e.g., contraction or constriction). o Glycogenolysis. o Gluconeogenesis. are equally sensitive to nor-epinephrine and epinephrine. However, only nor-epinephrine released from adrenergic neurons is present in high enough concentrations to activate ά1 receptors. Mechanism of action: Gq protein, stimulation of phospholipase C, and increase in inositol l,4,5-triphosphate (IP3) and intracellular [Ca2+]. 2. ά2 Receptors which are located in: o presynaptic nerve terminals. o platelets. o fat cells. o pancreatic beta cell. o vascular smooth muscles and the walls of the GI tract. Which produce: o inhibition (e.g., relaxation or dilation). o decrease insulin secretion. o platelet aggregation. o release of norepinephrine. Mechanism of action: Gi protein inhibition of adenylate cyclase and decrease in cyclic adenosine monophosphate (cAMP). All 3 beta receptors Mechanism of action are stimulated by Gs and increase cAMP. 3. β1 Receptors which are located in: o the sinoatrial (SA) node. o atrioventricular (AV) node. o ventricular muscle of the heart. o juxta-glomerular cell in the kidney Which produce: excitation increased (heart rate, conduction velocity at AV node, contractility of heart, renin secretion). are sensitive to both nor-epinephrine and epinephrine and are more sensitive than the alpha one receptor. 4. β2 Receptors which are located in: o vascular smooth muscle of skeletal muscle. o bronchial smooth muscle. o the walls of the GI tract and bladder. Which produce: relaxation (e.g., dilation of vascular smooth muscle, dilation of bronchioles, and relaxation of the bladder wall), glycogenolysis, uptake of potassium. are more sensitive to epinephrine than to nor-epinephrine. are more sensitive to epinephrine than the ά1 receptors. 5. β3 Receptors located in adipose tissue and involve in lipolysis. may be involved in regulating the metabolism of fatty acids. could be the site of anti-obesity drugs in the future. The function of the beta 4 receptor remains to be discovered. 2. Cholinergic receptors (choline-receptors) Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by: o o o o o o the terminals of the large pyramidal cells from the motor cortex, several different types of neurons in the basal ganglia, the motor neurons that innervate the skeletal muscles, the preganglionic neurons of the autonomic nervous system, the postganglionic neurons of the parasympathetic nervous system, and some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect; however, acetylcholine is known to have inhibitory effects at some peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves. A. Nicotinic cholinergic receptors: o Respond to nicotine and acetylcholine. o Ionotropic (ionic channel). o produce excitation. which are located in: o the neuromuscular junction (NM or N1). o the autonomic ganglia of the sympathetic and parasympathetic nervous systems, CNS, and adrenal medulla (NN or N2). The cholinergic receptors form a central channel (ion channels) When an agonist binds to the site and activated, all present subunits undergo a conformational change ►the channel is opened and a pore with a diameter of about 0.65 nm opens ► permits the passage of Na+, K+, and even Ca 2+. Structure: 1. The muscle subtypes receptors found at the neuromuscular junction, receptors are either o The embryonic form, composed of α1, β1, γ, and δ subunits in a 2:1:1:1 ratio ((α1)2β1γδ). o The adult form composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio ((α1)2β1δε). In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface. 2. The neuronal subtypes receptors o various homomeric (all one type of subunit). o heteromeric (at least one α and one β) combinations of twelve different nicotinic receptor subunits: α2−α10 and β2−β4. Examples of the neuronal subtypes include: (α4)3(β2)2, (α4)2(β2)3, (α3)2(β4)3, α4α6β3(β2)2, (α7)5, and many others. In neuronal nAChRs, the binding site is located at the interface of an α and a β subunit or between two α subunits in the case of α7 receptors. B. Muscarinic cholinergic receptors The substance known as muscarine from mushroom (amatina muscaria) is activating these types of receptors, so named as muscarinic receptors. Muscarinic receptor: o Respond to muscarine and acetylcholine. o Metabotropic (G-protein-coupled receptor). o Five subtypes of muscarinic receptors have been determined, named M1–M5 M1, M3, M5 receptors are coupled with Gq Proteins. Activation of phospholipase C(PLC), IP3 (inositol triphosphate), DAG (Diacylglycerol) M2, and M4 receptors are coupled with Gi/s proteins. Adenyl cyclase cAMP, upregulation down regulation. M1 receptor This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in salivary gland, enteric nerves and in the CNS. It is predominantly found bound to Gq Proteins, which use upregulation of phospholipase C(PLC), IP3 (inositol triphosphate), DAG (Diacylglycerol) and intracellular calcium as a signaling pathway. M2 receptor The M2 muscarinic receptors are found in the heart and lung, smooth muscle. M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage-gated Ca2+ channels, and increasing efflux of K+, in general, leading to inhibitory-type effects. M3 receptor The M3 muscarinic receptors found in the smooth muscles of the (airway, GIT, Bladder, eye), and (salivary, gastric, sweat) gland. Because the M3 receptor is Gq-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide. M4 receptor M4 receptors are found in the brain, lung. M4 receptors work via Gi receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. M5 receptor Location of M5 receptors is not well known. It is predominantly found bound to Gq Proteins, which use upregulation of phospholipase C(PLC), IP3 (inositol triphosphate), DAG (Diacylglycerol) and intracellular calcium as a signaling pathway. There are several areas of brain which are concerned with autonomic regulation: (1) Some of voluntary reflexes like the voiding of urine and defecation are controlled by cortical centers. (2) Hypothalamus Posterior hypothalamus regulate sympathetic function . anterior hypothalamus regulate parasympathetic function though there is overlapping in distribution of hypothalamus nuclei. ✓ Temperature regulation center. ✓ Thirst and food intake regulatory centers. (3) Autonomic centers-brain stem 1. Medulla (Vasomotor center, Respiratory center, Swallowing ,Coughing ,vomiting centers) 2. Pons (Pneumotaxic center) 3. Midbrain (Micturition center) (4) Center in the cranial nerve nuclei and spinal cord (5) The limbic system along with the hypothalamus produce the autonomic responses that accompany states and activity such as: Feeding and drinking behavior, sexual behavior and fear and rage reaction. The autonomic nervous system also often operates through visceral reflexes. That is, subconscious sensory signals from visceral organs can enter the autonomic ganglia, the brain stem, or the hypothalamus and then return subconscious reflex responses directly back to the visceral organs to control their activities. Transmission in sympathetic ganglia: The responses produced in post-gaglionic neurons by stimulation of their pre-ganglionic innervations include the following: o Fast excitatory post-synaptic potential: rapid depolarization that generate action potentials. o Slow inhibitory post-synaptic potential: a prolonged inhibitory depolarization that generate action potentials. o Slow excitatory post-synaptic potential: a prolonged excitatory depolarization that generate action potentials. o Late slow excitatory post-synaptic potential: It is very prolonged, lasting minutes rather than milliseconds. Cholinergic discharge: In general way, the functions promoted by activity in the cholinergic division of the autonomic nervous system are those concerned with vegetative aspects of day-today living. Vegetative functions are those bodily processes most directly concerned with maintenance of life. This category encompasses nutritional, metabolic, and endocrine functions including eating, sleeping, menstruation, bowel function, bladder activity, and sexual performance. Nor-adrenergic discharge: The nor-adrenergic division discharge as a unit in emergency situation. The effects of this discharge are of considerable value in preparing the individual to cope with the emergency, For example, nor-adrenergic discharge: 1. Relaxes accommodation and dilates the pupils (letting more light into the eye). 2. Accelerates the heartbeat and raise the blood pressure (providing better perfusion of the vital organs and muscles). 3. Constricts the blood vessels of the skin (which limits bleeding from wound). 4. Lower thresholds in the reticular formation (reinforcing the alert, aroused state). 5. Elevate plasma glucose and fatty acids level (supplying more energy). On the basis of effects like these, Cannon called the emergency-induced discharge of the nor-adrenergic nervous system the “preparation for fight or flight”. The emphasis on mass discharge in stressful situation should not obscure the fact that the nor-adrenergic autonomic fibers also sub-serve other functions. For example: tonic nor-adrenergic discharge to the arterioles maintains arterial pressure, In addition, sympathetic discharge is decreased in fasting animals and increased when fasting animals are re-fed. These changes may explain the decrease in blood pressure and metabolic rate produced by fasting and the opposite changes produced by feeding. ➢ Sympathetic concern with emergency, catabolic, alert, stress called the “catabolic” nor-adrenergic division. ➢ Parasympathetic concern with rest, digestion, anabolism, calm called the cholinergic division is sometimes called the “anabolic nervous system”. Sympathetic and parasympathetic tone: Normally, the sympathetic and parasympathetic systems are continually active, and the basal rates of activity are known, respectively, as sympathetic tone and parasympathetic tone. The value of tone is that it allows a single nervous system to both increase and decrease the activity of a stimulated organ. For instance, sympathetic tone normally keeps almost all the systemic arterioles constricted to about one-half their maximum diameter. By increasing the degree of sympathetic stimulation above normal, these vessels can be constricted even more; conversely, by decreasing the stimulation below normal, the arterioles can be dilated. ➢ Tone Caused by Basal Secretion of Epinephrine and Norepinephrine by the Adrenal Medullae. The normal resting rate of secretion by the adrenal medullae is about 0.2 μg/kg/min of epinephrine and about 0.05 μg/kg/min of norepinephrine. These quantities are considerable indeed, enough to maintain the blood pressure almost normal even if all direct sympathetic pathways to the cardiovascular system are removed. Effect of Loss of Sympathetic or Parasympathetic Tone After Denervation Immediately after a sympathetic or parasympathetic nerve is cut, the innervated organ loses its tone. In the case of the blood vessels, for instance, cutting the sympathetic nerves results immediately in almost maximal vasodilatation within 5 to 30 seconds. However, over minutes to days, “intrinsic tone” in the smooth muscle of the vessels increased. Increased tone caused by increased muscle contractile force that is not the result of sympathetic stimulation but chemical adaptation in smooth muscle fibers themselves. During the first week or so after a sympathetic or parasympathetic nerve is destroyed, the innervated organ become more sensitive to injected nor-adrenaline or acetylcholine. This phenomenon is called “denervation super-sensitivity”. The cause of denervation super-sensitivity is only partially known. Part of the answer is that the number of receptors in post-synaptic membrane of the effectors cells increases when nor-adrenaline or acetylcholine is no longer release in the synapses “up-regulation”. Therefore, when a dose of the hormone is now injected into the circulation, the effectors reactions are vastly increased. For instance, loss of parasympathetic tone to the heart after cardiac vagotomy increases the heart rate to 160 beats/min in a dog, and this rate will still be partially elevated 6 months later.