Autonomic Nervous System –An Introduction

The central nervous system is divided into:

1. Somatic system –voluntary
2. Autonomic system –involuntary

Autonomic nervous system is further classified into sympathetic and parasympathetic nervous system. Both originate from the brain and spinal cord. Parasympathetic nervous system has craniosacral origin (III, VII, IX, X, S3 and S4) while sympathetic nervous system has thoracolumbar origin. Fibers of both sympathetic and parasympathetic origins leave the CNS (fibers leaving CNS are called preganglionic fibers) and reach the ganglia, which lie outside the CNS. Postganglionic fibers arise from the ganglia to reach the effector organs.

Differences between pre-synaptic and post-synaptic fibers in sympathetic and parasympathetic systems

Parasympathetic system	Sympathetic system
Pre-synaptic fibers are long	Pre-synaptic fibers are short
Post-synaptic fibers are short	Post-synaptic fibers are long
Ganglia lie close to effector organs	Ganglia lie adjacent to spinal column
Preganglionic fibers synapse with a few post ganglionic fibers	Preganglionic fibers synapse with a lot of postganglionic fibers
Mostly local effect	More generalized effect (mass action)
	Ergotropic system (expenditure of energy)

Thus it can be said that the sympathetic fibers are primitive while the parasympathetic fibers are more advanced.

All nerves use chemicals for the transmission of impulses. These chemicals are present at the level of the ganglia and the junction of post ganglionic fibers to the effector organs. These chemicals are known as neurotransmitters and are released by nerve fibers

There are two main types of neurotransmitters:

1. Acetylcholine –released from cholinergic nerve fibers
2. Noradrenaline –released from adrenergic nerve fibers

At the level of the autonomic ganglia, the neurotransmitter is always acetylcholine whether sympathetic or parasympathetic, while at the level of the post ganglionic nerve fibers, the neurotransmitter is acetylcholine in case of parasympathetics. Sympathetics release noradrenaline but there are some exceptions i.e. sweat glands and some blood vessels release acetyl choline.

Non adrenergic and non cholinergic fibers do not release acetyl choline or noradrenaline. In these cases the exact role of neurotransmitters is not established but increased levels of NO, encephalins, endogenous opoids, endorphins, substance P, cholecystokinin may be found in some NANC fibers. Most probable neurotransmitter is the NO.

Most of the organs contain both sympathetic and parasympathetic fibers. Sympathetic fibers are concerned with fight or flight, increased heart rate, increased blood pressure, dilatation of pupils and increased glucose levels. The effects are generalized.

Parasympathetics are concerned with day to day functions and responses including repair and vegetative functions. In different organs either sympathetic or parasympathetic system may be acting more than the other.

The neurotransmitters are released in a definite sequence.

Generalized Mechanism

1. Synthesis of neurotransmitter. The precursor compound should enter the nerve terminal. Precursor compound in case of noradrenaline is tyrosine while that in case of acetylcholine is choline. Thus the neurotransmitter is formed.
2. Neurotransmitter after synthesis is stored in the vesicles.
3. When the nerve impulse reaches and stimulates the nerve fibers, entry of Ca++ causes release of neurotransmitter by exocytosis into the synaptic cleft.
4. After release, the neurotransmitter goes to the post synaptic membrane and the receptor is stimulated.

Acetylcholine                    Cholinergic receptors

Noradrenaline                    Adrenergic receptors

Neurotransmitter binds the receptors and stimulates them. Conformational change takes place and the effect is produced.

After producing the effect, neurotransmitter has two fates:

1. Acetylcholine is rapidly hydrolyzed by acetylcholine esterase enzyme
2. 80-90% of noradrenaline is reuptake by nerve fibers, and the cycle goes on

Cholinergic System

Acetylcholine is the main neurotransmitter. It is released at various sites:

1. All post ganglionic parasympathetic fibers
2. Autonomic ganglia
3. NMJ
4. Sympathetic fibers i.e. sweat glands and some blood vessels
5. Preganglionic fibers of adrenal medulla
6. In brain
7. Certain organs unrelated to the nerve fibers e.g. certain cells in placenta
8. Certain ciliated epithelial cells.

In the organs unrelated to the nerve fibers and certain ciliated epithelial cells it acts as a local hormone or autocoid and not as a neurotransmitter.

Steps:

1. Entry of precursor –choline enters the nerve terminals. Choline is transported into nerve by active process involving carrier molecule.
2. After entry into nerve fiber, it binds acetyl CoA

Choline + Acetyl CoA       in presence of CAT forms              Acetyl choline + CoA

3. Acetylcholine is stored in vesicles; there are about 100 to 50 thousand vesicles in one nerve terminal. In cholinergic terminals two types of vesicles are found:

a. Large number of small clear vesicles containing acetyl choline lying near the synaptic end of nerve terminal.

b. Small number of large vesicles containing peptides not acetyl choline

Drug which blocks entry of acetylcholine into  vesicles is known as vesamicol. Hemicholinium blocks the entry of choline into the nerve terminals.

4. When nerve fiber is stimulated, release of acetyl choline from vesicles takes place by virtue of entry of Ca++. The role of calcium is that it causes instability of various membrane bound proteins. The vesicles associated with membrane bound proteins (VAMP) lead to release by a process of exocytosis.

5. When acetyl choline is released in to the cleft it diffuses to post synaptic membrane and binds cholinergic receptors. Two types of receptors are found:

1. Muscarinic receptors
2. Nicotinic receptors

Characteristics for the most important cholinoceptors in the peripheral nervous system

RECEPTORS	LOCATION	MECHANISM	MAJOR FUNCTIONS
M1	Nerve endings, autonomic ganglia and stomach (pyrazinamide used ulcer treatment )	Gq-coupled	IP3, DAG cascade
M2	Heart, some nerve endings	Gq-coupled	cAMP, activates K+ channel
M3	Effector cells: smooth muscle, glands, endothelium	Gq-coupled	IP3, DAG cascade
NN	ANS ganglia	Ion channel	Depolarizes, evokes action potential
NM	Neuromuscular end plate	Ion channel	Depolarizes, evokes action potential

Various antagonists to which response occurs are 5 types of muscaranic receptors (2 types of nicotinic receptors are found according to antagonist; NN mainly present in nerve or autonomic ganglia and NM in the muscles).

M1, M3 and M5 are excitatory muscarinic receptors

M2 and M4 are inhibitory muscarinic receptors (M2 are found in heart)

After binding to receptor, inactivation occurs. Acetyl choline esterase in synaptic cleft causes hydrolysis of acetyl choline into choline and acetic acid. There are two types of choline esterases:

1. True choline esterase –mainly present in synaptic cleft and plasma responsible for most of the degradation.
2. Pseudo choline esterase –Synthesized in liver and present in plasma, responsible for degradation of acetyl choline as well as skeletal muscle relaxant e.g. suxamethonium (NMJ blocker used in anesthetics)

When pseudocholine esterase is deficient (e.g. liver disease, starvation, malnutrition, genetically atypical) then suxamethonium is not metabolized and has prolonged effects (may cause respiratory apnea). Both true and pseudo choline esterases metabolize acetylcholine.

Acetyl choline esterase –Method of Degradation

Acetyl choline esterase has two parts; anionic and esteretic. Acetyl choline molecule also has two parts; carboxyl and acetyl. Carboxyl part binds anionic site, while acetyl part binds esteretic site.

When acetyl choline binds, acetylation of esteretic site occurs and choline is released. Acetyl group reacts with water to form acetic acid. Esteretic site is again exposed and a new molecule binds, the cycle continues.

Acetyl choline is hydrolyzed very rapidly (in msec) and thus has no use in therapeutics. Only analogs of acetyl choline (synthetic) are used because of short duration of action of acetyl choline.

Adrenergic System

Nor epinephrine or nor adrenaline is released from the post ganglionic sympathetic fibers except sweat glands and some blood vessels. It is synthesized in the nerve terminals. The precursor is tyrosine.

Tyrosine is converted by tyrosine hydroxylase into DOPA. DOPA is converted by DOPA decarboxylase into Dopamine. Dopamine is converted by  dopamine β hydroxylase  into Noradrenaline. Noradrenaline is converted into Adrenaline by addition of methyl group.

Adrenaline is synthesized in the adrenal medulla and not in nerve terminals.

After formation, the neurotransmitters are stored in the form of vesicles. The mechanism for production is regulated. The regulation is by two mechanisms:

1. Positive feedback –as more released, more are formed
2. Negative feedback by:
   1. Tyrosine hydroxylase
   2. Alpha 2 receptors

Effect of alpha 2 receptors is opposite to that of alpha 1 receptors. Alpha 2 receptors are the catecholamines regulatory receptors.

Due to decreased release of noradrenaline, adenyl cyclase is inhibited which decreases cAMP levels.

Alpha 2 agonists are used in treatment of hypertension (e.g. alpha methyl dopa, clonidine)

1. Through regulatory heteroceptors, stimulated by substances released from other nerve fibers, e.g. myocardium cholinergic fibers and vagal fibers have communication with the sympathetic fibers and cause a decrease in the release of noradrenaline.

Antagonist of tyrosine hydroxylase is metyrosine.

After synthesis neurotransmitters stored in vesicles are in combination with ATP in the ratio 4:1, also proteins are present. Stimulation of nerve fiber by entry of Ca++ causes exocytosis of noradrenaline.

When released, diffuses through the synaptic cleft to reach the adrenergic receptors to cause stimulation.

Alpha adrenergic   1, 2

Beta adrenergic    1, 2, 3

Dopa receptors      D1, 2,3,4,5

Alpha 1	Alpha 2 (pre-synaptic)	Beta 1 (pre-synaptic)	Beta 2	Beta 3
Vasoconstriction Increased TPR Increased blood pressure	Inhibits nor epinephrine release (due to negative feedback)	Positive ionotropic effect	Vasodilatation, with decreased TPR	Increased lipolysis
Mydriasis	Reduces acetylcholine release	Positive chronotropic effect, may lead to tachycardia	Bronchodilatation
Closure or constriction of sphincters of GIT and urinary bladder	Reduces lipolysis	Increased renin release	Increased release of glucagon
Erection of hair Pilomotor smooth muscles	Reduces insulin release	Increased lipolysis	Increased uptake of K+ into sk. muscle cells
	Platelet aggregation		Relaxation of uterine smooth muscles
			Increased glycogenolysis in muscles, liver
			Relaxation of smooth muscles of GIT and urinary bladder