Essentials and Pharmacological

Peripheral Nervous Systemy Handles

the CNSs input and output. y Contains all the portions of the NS outside the brain and spinal cord. y Contains sensory nerves and motor nerves y Divided into autonomic nervous system and somatic nervous system.

Peripheral Nervous Systemy

Sensory Nerves (to the brain)

y

Motor Nerves (from the brain)

Carry messages from Carry orders from CNS receptors in the skin, to muscles, glands to muscles, and other contract and produce internal and external chemical sense organs to the messengers spinal cord and then to the brain

The ANS is part of the peripheral nervous system and it controls many organs and muscles within the body. y In most situations, we are unaware of the workings of the ANS because it functions in an involuntary, reflexive manner. y For example, we do not notice when blood vessels change size or when our heart beats faster. y However, some people can be trained to control some functions of the ANS such as heart rate or blood pressure.y

The ANS is most important in two situations: 1- In

emergencies that cause stress and require us to "fight" or take "flight" (run away).

2- In no emergencies that allow us to "rest" and "digest".

y It

is usual to divide the nervous system into somatic, autonomic and integrated systems. y The somatic nervous system provides voluntary motor control of skeletal muscle. y The autonomic nervous system provides an involuntary control of internal environment and the viscera.

y The

two systems are anatomically separated form each other, but functionally they cannot perform their work independently, and they work with each other in an integrated manner

Peripheral Nervous Systemy

Somatic NS

y

Autonomic NS

Consists of nerves connected to sensory receptors and skeletal muscles Permits voluntary action (writing your name)

Permits the Involuntary functions of blood vessels, Glands and internal organs e.g.:the bladder stomach heart

Characteristic Effectors General functions

Somatic nervous system Voluntary muscle

Autonomic N. system Cardiac muscle glands, s. muscle

Adjustment to Adjustment within external environment internal environment 2 Chain ganglia, collateral ganglia or terminal ganglia Acetylcholine, adrenaline, noradrenaline Lateral Horn cells

Numbers of neurons 1 Ganglia outside the -----------CNS Neurotransmitter acetylcholine

Center

Anterior Horn cells

Comparison of Autonomic and Somatic Motor Systemsy

Autonomic nervous systemChain of two motor neuronsx Preganglionic neuron x Postganglionic neuron

Conduction is slower due to thinly or unmyelinated axons

Pre-ganglionic Ganglion

Post-ganglionic

Sympathetic N.S.

Parasympathetic N.S.

Like the accelerator of your car

Like the brakes in your car Slows the body down to keep its rhythm Enables the body to conserve and store energyPreganglionic: long, synapse within the terminal ganglia Postganglionic: short Has a restricted distributions

Mobilized the body for actionPreganglionic: short, synapse within the lateral & collateral ganglia Postganglionic: long Has a wide distributions

Often work in opposition Cooperate to finetune homeostasis Regulated by the brain; hypothalamus, pons and medulla Can also be regulated by spinal reflexes; no higher order input Pathways both consist of a two neuron systemPreganglionic neuron from CNS

Autonomic Nervous System

autonomic ganglion outside CNS

postganglionic neuron

target

Hypothalamus activates Fig. 45.34(TE Art) sympathetic division of nervous system Heart rate, blood pressure, and respiration increase Adrenal medulla secretes epinephrine and norepinephrine

Stomach Blood flow to skeletal muscles contractions are inhibited increases

SympatheticFight or Flight, Dealing with stress, thoracolumber, intermediolateral column, T1 -L2

Parasympathetic Rest and Digest,Craniosacral S2-S4,

Sympathetic nerve endings also activate the release of NE and E from the adrenal medulla Enhances effects of NE from sympathetic nerve endings Adds the effects of E to the overall arousal (fight or flight) pattern

The Autonomic System

Sympathetic Sometimes called the thoracolumbar division Short preganglionic neurons; long postganglionic neurons; ganglia are called the chain ganglia Preganglionic neurons secrete Ach onto nicotinic receptors Postganglionic neurons secrete NE on to E or F receptors Target tissues are smooth muscle, cardiac muscle, endocrine glands, brown fat

Parasympathetic Sometimes called the cranio-sacral division Long preganglionic neurons; short postganglionic neurons (often in the target organ) Preganglionic neurons secrete Ach on to nicotinic receptors Postganglionic neurons secrete Ach on to muscarinic receptors Target tissues are smooth muscle, cardiac muscle, exocrine glands, brown fat

Anatomical Differences in Sympathetic and Parasympathetic Divisions

Anatomical Differences in Sympathetic and Parasympathetic Divisions

Similarities between Sympathetic & Parasympathetic Both are efferent (motor) systems: visceromotor

Both involve regulation of the internal environment generally outside of our conscious control: autonomous Both involve 2 neurons that synapse in a peripheral ganglion and Innervate glands, smooth muscle, cardiac muscleglands CNS ganglion smooth muscle preganglionic neuron postganglionic neuron cardiac muscle

Differences between Sympathetic & Parasympathetic Location of Preganglionic Cell Bodies

Sympathetic ThoracolumbarT1 L2/L3 levels of the spinal cord

Parasympathetic CraniosacralBrain: CN III, VII, IX, X Spinal cord: S2 S4

Differences between Sympathetic & Parasympathetic SympatheticCNS

Relative Lengths of Neuronsganglion target

short preganglionic neuron

long postganglionic neuron

ParasympatheticCNS ganglion

target

long preganglionic neuron

short postganglionic neuron

Overview of the Autonomic Nervous SystemDifferences between Sympathetic & Parasympathetic Neurotransmitters NE (ACh at sweat glands), SympatheticACh, + + / -, & receptors

All preganglionics release acetylcholine (ACh) & are excitatory (+) Symp. postgangl. norepinephrine (NE) & are excitatory (+) or inhibitory (-) Excitation or inhibition is a receptor-dependent & receptor-mediated response

Parasympathetic

ACh, +

ACh, + / muscarinic receptors

Parasymp. postgangl. ACh & are excitatory (+) or inhibitory (-)

Overview of the Autonomic Nervous SystemDifferences between Sympathetic & Parasympathetic Target Tissues Sympathetic Parasympathetic Organs of head, neck, Organs of head, neck, trunk, & external genitalia trunk, & external genitalia Adrenal medulla Sweat glands in skin Arrector muscles of hair ALL vascular smooth muscle Sympathetic system is distributed to essentially all tissues (because of vascular smooth muscle) Parasympathetic system never reaches limbs or body wall (except for external genitalia)

Overview of ANSFunctional Differences Sympathetic Fight or flight Catabolic (expend energy)

Parasympathetic Feed & breed, rest & digest Homeostasis

Dual innervation of many organs having a brake and an accelerator provides more control

Chemical transmissionThe traveling of signal in the nervous system between different neurons is mediated by the effect of a chemical substance released at the nerve terminal called chemical transmitter. In the sympathetic nervous system the chemical transmitter is adrenaline, noradrenaline or sometimes acetylcholine. When the chemical transmitter is adrenaline the nerve fiber is called adrenergic, but when the chemical transmitter is acetylcholine, the nerve fiber is called cholinergic.

Nerves Contact Other Cells at Synapsesy

y

y

y

The synapse is the relay point where information is conveyed from neuron to neuron by chemical transmitters. At a synapse the axon usually enlarges to from a button ' which is the information delivering part of the junction. The terminal button contains tiny spherical structures called synaptic vesicles, each of which can hold several thousand molecules of chemical transmitter. On the arrival of a nerve impulse at the terminal button, some the vesicles discharge their contents into the narrow cleft that separates the membrane of another cell's dendrite, which is designated to receive the chemical message.

y Chemical

transmitters carry the signal across synapses y Chemical transmitters are made and stored in the presynaptic terminal y The transmitter diffuses across the synaptic gap and binds to a receptor in the postsynaptic membrane. y Binding of the Transmitter Produces an excitatory postsynaptic potential EPSP or inhibitory postsynaptic potential IPSP

The Transmitter is Broken down and Recycled y Once the signal has been delivered the transmitter must be removed so that new signals may be received y In some cases the transmitter is broken down by an enzyme in the synapse y In other cases the transmitter is recycledit is transported back into the presynaptic nerve y In still other cases these 2 methods are combined

Acetylcholine y Important neurotransmitter in central and peripheral nervous systems. y Acetylcholine is synthesized in the nerve terminal. 1- Acetyl-coenzyme A (AcCoA) is manufacured in mitochondria. 2- Choline is accumulated in the teminals by active uptake from interstitial fluid. 3- AcCoA + choline = acetylcholine.

Acetylcholine storagey

Acetylcholine is stored in vesciles in the verve terminal after its synthesis, each vesicle contains approximatly 104 Ach molecules, which are released as a single packet. Acetylcholine release The arrival of the action potential to the nerve terminal, it leads to increase in the permeability of the terminal to Ca++ influx. y Ca++ recat with synapsin that bind the vesciles, which on its unbinding the vesciles sweeps to attach to the presynaptic membrane. y The vesciles rupture and the acetylcholine released to the synaptic cleft. y Acetylcholine act on its specific receptors on the postsynaptic membrane.

Acetylcholine release sites 1-Preganglionic nerve fibres of both sympathetic and parasympathetic divisions of the autonomic nervous system. 2-Postganglionic nerves of the parasympathetic division. 3- The sympathetic innervation of sweet glands. 4- Neuromuscular junction. 5- Autonomic ganglion to the adrenal gland.

Neurotransmitter release sites

Acetylcholine inactivation In synaptic cleft, Acetylcholinesterase breaks it down into acetate and choline.

50% of choline then re up taken into presynaptic neuron.

Acetylcholine receptorsAcetylcholine effects on the tissue are the result of its action on the receptor present in the membrane of the effector cells. Several types of Ach receptors have been characterized by their sensetivity to agonists (which mimic the action of Ach) or antagonists (which specifically block the action of Ach). y Two types of cholinergic receptors are well known: y Nicotinic receptors which are easily activated by agonist molocule such as nicotine and y Muscarinic receptors: which are sensitive to muscarine.

Cholinergic receptorsNicotinic receptors (Central) Types Two types:Ganglionic Neruomuscular Nicotine in small doses, Ach, metacholine Muscarinic receptors (peripheral ) M1, M2 (cardiac), M3 (glandular&smooth muscle) M4 (brain).M5,M6 and M7. Muscarine, Ach, carbarcholine

Stimulated by Blocked by

Nicoitin in large doses- Atropine decameyhonium scopolamine d-tubourarineAutonomic ganglia M.E.P Adrenal medulla Preganglionic neuron. Parasympathetic (pre-postganglionic) Sympathetic postganglionic nerve endings (sweat glands & skeletal muscle).

site

Nicotinic ReceptorsLocated in the ganglia of both the PSNS and SNS y Named nicotinic because can be stimulated by the alkaloid nicotiney

Muscarinic Receptorsy

Located postsynaptically:Smooth muscle Cardiac muscle Glands of parasympathetic fibers Effector organs of cholinergic sympathetic fibers

y

Named muscarinic because can be stimulated by the alkaloid muscarine

Parasympathetic (Cholinergic) Drugs

Subdivisions of the Autonomic Nervous System

Sympathetic

Parasympathetic

Primary Neurotransmitter Receptors & Second Messenger Systems

norepinephrine epinephrine (~20%) Adrenergic GPCRs E1 IP3/DAG, o[Ca2+]i oPKC E2 - qcAMP/PKAF1 - ocAMP/PKA F2 - ocAMP/PKA F3 - ocAMP/PKA

acetylcholine

Muscarinic GPCRs M1 IP3/DAG, o[Ca2+]i oPKC M2 qcAMP/PKA, oPI(3)K M3 qcAMP/PKA, IP3/DAG, o[Ca2+]i oPKC M4 M5 IP3/DAG, o[Ca2+]i oPKC

Adrenal Medulla (epi:norepi::80:20)

Comparison of sympathetic and Parasympathetic Pathways

Neurotransmitters y Receptorsy

Drugs Affecting the Autonomic Nervous SystemParasympathomimetic drugs: These are drugs which exert an action similar to acetylcholine and there are two types:- Drugs directly stimulate cholinergic receptors - Drugs inhibit cholinesterase enzyme. Parasympatholytic Drugs: These drugs antagonize the action of acetylcholine.

Cholinergic AgentsDrugs that stimulate the parasympathetic nervous system (PSNS). y Drugs that mimic the effects of the PSNS neurotransmitter y Acetylcholine (ACh)y

Parasympathomimetic drugs

These are drugs which exert an action similar to the action of acetylcholine and it is divided into two groups: (A) Drugs that directly stimulate the cholinergic receptors: These include Ach derivatives that not hydrolyzed rapidly by cholinesterase e.g. metacholine, carbachol, poiolocarpine and muscarine.

(B) Drugs that inhibit the cholinesterase enzyme: These drugs preserve the action of Ach by preventing the action of cholinesterase enzyme and they are two types:(1) Drugs which has a reversible effect i.e. their action is temporary e.g. eserine (phyostigmine) and prostigmine (neostigmine).x - Eserine: is a generalized drugs which causes generalized blocking allover the body, thus we use it locally as an eye drops in treatment of glaucoma otherwise it will cause generalized parasympathetic effect. - Neostigmine:It was used in treatment of myasthenia gravis due to its direct action on the motor end plate.

x

(2) Drugs which have irreversible effect i.e. their action are prolonged e.g. parathion (an insecticide) and D.F.P. (Diisopropyflurophosphate), which is a toxic nerve gas.

Parasympatholytic DrugsThese drugs which antagonize the action of Ach by one of the following mechanisms:y Competitive inhibition: These drugs occupy the Ach receptors and present its action. y Persistent depolarization: These drugs cause prolonged depolarization of Ach receptor thus they prevent the excitation of the receptor by the released Ach.y

Parasympatholytic drugsMuscarinic like action blockers These drugs block the action of Ach at cholinergic receptors by blocking the action of Ach at muscarinic receptors e.g.AtropineHomatropine Hyoscine Ganglion blockers These drugs block the action of Ach at nicotinic recpotors Neuromuscular blocker These drugs block the nicotinic like action of Ach at neuromuscular junction.

e.g. -Nicotine in large doses. - Arfonad - Hexamethonium Competitive inhibition. -Persistent depolarization

e.g. - curare

Mechanism of actioncompetitive inhibition Clinical use: Atropine used for:-dilation of pupil- relive spasm- prevent bronchial secretion

Competitive inhibition.

- Ganglion blocker used - Curare is used as a for blocking conduction in muscle relaxant sympathetic ganglion of hypertension.

Sympathetic (Adrenergic) Drugs

NADP+from phe, diet, or protein breakdown

NADPH DHBR

BH4 Tyrosine 1

BH2 L-Dopa Tyrosine hydroxylase 2 CO2(rate-determining step) H O 2

O2DPN OHase in neuroscretory granules

H2O

3 ascorbate

O2

Dopa decarboxylase pyridoxal phosphate

Norepinephrine Dopamine hydroxylase PNMT Epinephrine 4 SAM SAHPNMT specific to adrenal medulla

DopamineParkinsons disease: local deficiency of dopamine synthesis; L-dopa boosts production

SAM from metabolism of Met

Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin; DHBR,dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase; SAH, Sadenosylhomocysteine; SAM, S-adenosylmethionine

Regulation of the release of catecholamines and synthesis of epinephrine in the adrenal medulla chromaffin cell.

tress Chronic regulation Hypothalamus ACTH Cortisol Tyrosinefrom adrenal cortex via intraadrenal portal system

Acute regulation

L-Dopa

DPN induction

granule Neuron

.... . ... .... ... ...

Ca2+

DPN q NE

PNMT NE

Epinephrine neurosecretory granules

acetylcholine Adrenal Medulla Chromaffin Cell promotes exocytosis E EEE NE E E NE EE

Epinephrine Norepinephrine

COMT + MAO Vanillylmandelic acid

COMT + MAO Dopamine Homovanillic acid

Neuronal re-uptake and degradation of catecholamines quickly terminates hormonal or neurotransmitter activity. Cocaine binds to dopamine receptor to block re-uptake of dopamine Dopamine continues to stimulate receptors of the postsynaptic nerve.

Degradation of epinephrine, norepinephrine and dopamine via monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT)

Table 1. Classification of Adrenergic Hormone ReceptorsReceptor alpha1 (E1) alpha2 (E2) beta1 (F1) beta2 (F2) Agonists E>NE NE>E E=NE E>>NE Second Messenger IP3/Ca2+; DAGq cyclic AMP o cyclic AMP o cyclic AMP

G protein Gq Gi Gs Gs

E = epinephrine; NE = norepinephrine Synthetic agonists: isoproterenol binds to beta receptors phenylephrine binds to alpha receptors (nose spray action) Synthetic antagonists: propranolol binds to beta receptors phentolamine binds to alpha receptors

NH2

H

Figure 4. Model for the structure of the F2-adrenergic receptor

Table 2. Metabolic and muscle contraction responses to catecholamine binding to various adrenergic receptors. Responses in italics indicate decreases of the indicated process (i.e., decreased flux through a pathway or muscle relaxation)E1-receptor E 2receptor F 1receptor F2-receptor

Process (IP3, DAG) Carbohydrat o liver e glycogenolysis metabolism Fat metabolism Hormone secretion No effect No effect Smooth muscle - blood vessels, genitourinary tract

(q cAMP) No effect

(o cAMP) No effect

(o cAMP)oliver/muscle glycogenolysis; o liver gluconeogenesis; q glycogenesis

q lipolysis q insulin secretion

o lipolysis

No effecto insulin and glucagon secretion

No effect

Muscle contraction

Smooth muscle some vascular; GI tract relaxation

Myocardial -o rate, force

Smooth muscle relaxation - bronchi, blood vessels, GI tract, genitourinary tract

F1 or F2 receptor

E2 receptor

Gs

Gi

Es

F K

F K

F K

Ei EiGTP \ GTP

F K

GTP GT

Es

inactive adenylyl cyclase ATP

ACTIVE adenylyl cyclase

X

inactive adenylyl cyclase

cyclic AMP

Figure 5. Mechanisms of F1, F2, and E2 agonist effects on adenylyl cyclase activity

"FIGHT OR FLIGHT" RESPONSE epinephrine/ norepinephrine major elements in the "fight or flight" response acute, integrated adjustment of many complex processes in organs vital to the response (e.g., brain, muscles, cardiopulmonary system, liver) occurs at the expense of other organs less immediately involved (e.g., skin, GI).

epinephrine: rapidly mobilizes fatty acids as the primary fuel for muscle action increases muscle glycogenolysis mobilizes glucose for the brain by o hepatic glycogenolysis/ gluconeogenesis preserves glucose for CNS by q insulin release leading to reduced glucose uptake by muscle/ adipose increases cardiac output norepinephrine elicits responses of the CV system - o blood flow and q insulin secretion.

Figure 6. Mechanisms for terminating the signal generated by epinephrine binding to a F-adrenergic receptor epinephrine [1] dissociation

[2]

E GTP

K

F

EG P

degradation to VMA

AC

[5] GTPase [6]OH OH

[3]

[4]

ATP cAMP AMP phosphodiesterase

activated PKA phosphorylates enzymes

OP OP phosphorylation of F-receptor by F-ARK decreases activity even with bound hormone

OPOP binding of F-arrestin further inactivates receptor despite bound hormone

OH [7]

OP

insulin activation of protein phosphatase to dephosphorylate enzymes

&1 found on heart muscle and in certain cells of the kidney

B2 found in certain blood vessels, smooth muscle of airways; found where sympathetic neurons ARE NOT%1 receptors are found most commonly in sympathetic target tissues

A2 receptors are found in the GI tract and pancreas (relaxation)