NERVOUS SYSTEMThe nervous system detects and responds to changes inside and outside the body. Together with the endocrine system it controls important aspects of body function and maintains homeostasis. Nervous system stimulation provides an immediate response while endocrine activity is, In the main, slower and more prolonged.

The nervous system includes both the Central nervous system and Peripheral nervous system. The Central nervous system is made up of the brain and spinal cord and The Peripheral nervous system is made up of the Somatic and the Autonomic nervous systems.

The Peripheral nervous systemThe Peripheral nervous system is made up of two parts:

1. Somatic nervous system

2. Autonomic nervous system

Somatic nervous system(Voluntary muscles)

The somatic nervous system consists of peripheral nerve fibers that pick up sensory information or sensations from the peripheral or distant organs (those away from the brain like limbs) and carry them to the central nervous system.

These also consist of motor nerve fibers that come out of the brain and take the messages for movement and necessary action to the skeletal muscles. For example, on touching a hot object the sensory nerves carry information about the heat to the brain, which in turn, via the motor nerves, tells the muscles of the hand to withdraw it immediately.

The whole process takes less than a second to happen. The cell body of the neuron that carries the information often lies within the brain or spinal cord and projects directly to a skeletal muscle.

Autonomic nervous system(Involuntary muscles)

This nervous system controls the nerves of the inner organs of the body on which humans have noconscious control. This includes the heartbeat, digestion, breathing (except conscious breathing) etc.

The nerves of the autonomic nervous system enervate the smooth involuntary muscles of the (internalorgans) and glands and cause them to function and secrete their enzymes etc.

Differences between somatic and autonomic nervous system

The autonomic nervous system consists of three main anatomical divisions:

1. The sympathetic nervous system

2. The parasympathetic nervous system

3. The enteric nervous system

The sympathetic nervous system is activated in an emergency or stressful situation, and the effects are classified as ‘fight or flight’ responses. On the other hand, the parasympathetic division has a restorative function, and the effects are classified as ‘resting and digesting’ responses.

The enteric nervous system comprises the intrinsic nerveplexuses of the gastrointestinal tract, which are closely interconnected with the sympathetic and parasympathetic systems.

A degree of autonomic control also affects many other systems, including the kidney, immune system and somatosensorysystem.

The autonomic efferent pathway consists of two neurons arranged in series, whereas in the somatic motor system a single motor neuron connects the central nervous system to the skeletal muscle fiber.

The two neurons in the autonomic pathway are known, respectively, as preganglionic and postganglionic

The parasympathetic nervous system (PNS)

In parasympathetic pathways, the postganglionic cells are mainly found in the target organs, discrete parasympathetic ganglia (e.g. the ciliary ganglion) being found only in the head and neck.

Long preganglionic axons originate from neurons in the cranial and sacral areas of the spinal cord and, with few exceptions, synapse on neurons in ganglia located close to or within the innervated organ.

Short postganglionic axons innervate cardiac muscle, bronchial smooth muscle, and exocrine glands.

Parasympathetic innervation predominates over sympathetic innervations of salivary glands, lacrimal glands, and erectile tissue.

The sympathetic nervous system (SNS)

In the sympathetic nervous system, the intervening synapses lie in autonomic ganglia, which are outside the central nervous system, and contain the nerve endings of preganglionic fiber and the cell bodies of postganglionic neurons.

Short preganglionic axons originate from neurons in the thoracic and lumbar areas of the spinal cord and synapse on neurons in ganglia located outside of, but close to, the spinal cord. The adrenal medulla, anatomically considered a modified ganglion, is innervated by sympathetic preganglionic axons.

Long postganglionic axons innervate many of the same tissues and organs as the PNS.

Innervations of thermoregulatory sweat glands is anatomically sympathetic, but the postganglionic nerve fibers are cholinergic and release acetylcholine (ACh) as the neurotransmitter.

The enteric nervous system Considered a third branch of the ANS.

Highly organized, semiautonomous, neural complex localized in the gastrointestinal (GI) system.

Receives preganglionic axons from the PNS and postganglionic axons from the SNS .d. Nerve terminals contain peptides and purines as neurotransmitters.

The enteric nervous system consists of the neurons whose cell bodies lie in the intramural plexuses in the wall of the intestine.

Some enteric neurons function as mechanoreceptors or chemo receptors, providing local reflex pathways that can control gastrointestinal function without external inputs. The enteric nervous system is pharmacologically more complex than the sympathetic or parasympathetic systems, involving any neuropeptide and other transmitters (such as5-hydroxytryptamine, nitric oxide and ATP).

Cholinergic System (acetylcholine) and Drugs

AcetylcholineIt was discovered by Henry Hallett Dale in 1914, and its existence was later confirmed by Otto Loewi. Both individuals were awarded the Nobel Prize in Physiology/Medicine in 1936 for their discovery.

Acetylcholine (ACh) is a major neurohumoral transmitter at autonomic, somatic as well as central sites.

.Acetylcholine is an ester formed by the combination of choline and acetate and is synthesized by two steps.

First step is a uptake of choline from the extracellular fluid by means of an active transport system. Secondly, the formation of acetylcoenzyme-A (active from of acetate) inside the fiber in the presence of acetyl kinase.

Choline and acetylcoenzyme-A then react in the presence of choline acetyltransferase to form Ach.

Muscarinic actions closely resemble the effects of parasympathetic stimulation.

After the muscarinic effects have been blocked by atropine, larger doses of ACh produce nicotine-like effects, which include:

• Stimulation of all autonomic ganglia

• Stimulation of voluntary muscle

• Secretion of adrenaline from the adrenal medulla.

Storage

After synthesis, Ach is stored in to membrane bound vesicles.

These synaptic vesicles are concentrated in cholinergic nerve terminal.Release

Ach is released from nerve terminal in constant amount (quanta release) in the synaptic cleft and produces a spontaneous depolarization of motor end plate of the muscle.

But the magnitude of these miniature end plate potentials (MEPP) are small and are below the threshold level to produce a muscle action potential (AP).

Botulinum, a potent toxin produced by clostridium (and tetanus toxin) tetradotoxin from puffer (below) fish blocks the release of Ach from the nerve terminal. Death occurs due to respiratory failure.

Black spider toxin depletes Ach from the storage and thus produces excessive release and thus depletes the store. Inactivation

Ach is an ester and is hydrolyzed in to choline and acetic acid by enzyme cholinesterase (ChE).

Cholinesterase is mainly responsible for quick inactivation of Ach.

Cholinesterases are of two types

Acetylcholinesterase (True cholinesterase) Butyrylcholinesterase (Pseudo cholinesterase)

Differences between the two types of cholinesterase

ACETYLCHOLINE RECEPTORS

Two classes of receptors for ACh are recognized-

Muscarinic receptors Nicotinic receptors

Muscarinic receptors

Muscarinic acetylcholine receptors (mAChRs) belong to the class of G protein–coupled receptors.

G protein–coupled receptors means GTP activated protein.These receptors are selectively stimulated by muscarine and blocked by atropine.

The effect of acetylcholine at the postganglionic parasympathetic nerve ending is called muscarinic receptors/action.

The muscarinic action of acetylcholine are-

Decrease in heath rate (bradycardia) Increase in glandular secretions like salivary and other

gastrointestinal secretions. Contraction of smooth muscle like intestine and bronchi.

Subtypes of muscarinic receptor

Muscarinic receptors have been divided into 5 subtypes M1, M2, M3, M4 and M5. The first 3 are the major subtypes M1, M2 and M3.

M1 RECEPTORS

The M1 is primarily a neuronal receptor located on ganglion cells and central neurons.

These are G protein coupled receptors and act through IP3/DAG mechanism by increasing cytosolic calcium in cell.

They mediate excitatory effects, for example the slow muscarinic excitation mediated by ACh in sympathetic ganglia and central neurons. This excitation is produced by a decrease in K+ conductance, which causes membrane depolarisation.

Deficiency of this kind of ACh-mediated effect in the brain is possibly associated with dementia, although transgenic M1 receptor knockout mice show only slight cognitive impairment.

M1 receptors are also involved in the increase of gastric acid secretion following vagal stimulation.

M2 receptors

The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm, by slowing the speed of depolarization.

Cardiac muscarinic receptors are predominantly M2 and mediate vagal bradycardia. Auto receptors on cholinergic nerve endings are also of M2 subtype. Smooth muscles express some M2 receptors as well which, like M3, mediate contraction.

These are G protein coupled receptors and act by opening k+ channels or by reducing cyclic AMP

M3 receptors

The M3 muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M3 receptor is Gq-coupled and mediates an increase in intracellular calcium

M3 muscarinic receptors are associated with visceral smooth muscle and exocrine glands.

Stimulation of these receptors causes the following parasympathetic-like effects:

Pupil constriction (miosis) and increased rate of drainage of aqueous humour from the anterior cavity of the eye.

Relaxation of gastrointestinal sphincters, increased gastrointestinal motility and an increased secretion of digestive juices (saliva, pancreatic juice and bile).

Promotion of micturition and defecation. Promotion of glycogenesis and gluconeogenesis (increases insulin

secretion). Promotion of lacrimal secretion (tears). Bronchoconstriction and increased bronchial mucus secretion.

Stimulation of these receptors induces the following sympathetic responses:

Vasoconstriction of blood vessels associated with the skin and external genitalia.

Vasodilation of blood vessels to skeletal muscle. Generalised sweating.

Table for Characteristics of important subtypes of muscarinic receptor

Common adverse effects

Figures- A, B and C show the effects, both therapeutic and adverse, of muscarinic receptor stimulation.

Figure - A Flowchart showing the effects of muscarinic receptor (M1 and M2) agonists

Figure - B Flowchart showing the effects of muscarinic receptor (M3) agonists

Figure - C The effects of muscarinic receptor agonists

Figure D summarises the agonist effects associated with the stimulation of all types of peripheral cholinergic receptors. Common adverse effects depend on the desired clinical effect but can include bradycardia, hypotension, pupil constriction, sweating, bronchoconstriction, drooling and diarrhoea. Contraindications include intestinal and urinary obstruction.

Figure - D Cholinergic agonist effects

M4 and M5 receptors are largely confined to the CNS, and their functional role is not well understood, although mice lacking these receptors do show behavioural changes.

Recently it has been discovered that cytokine secretion from lymphocytes and other cells is regulated by M1 and M3 receptors, while M2 and M4 receptors affect cell proliferation in various situations, opening up hitherto unsuspected therapeutic roles for muscarine receptor ligands.

The agonist binding region is highly conserved between the different subtypes, so attempts to develop selective agonists and antagonists have had limited success. Most known agonists are non-selective, though two experimental compounds, McNA343 and oxotremorine, are selective for M1 receptors, on which carbachol is relatively inactive.

Other M1 selective agents (e.g. xanomeline) are in developmentas possible treatments for dementia.

There is more selectivity among antagonists. Althoughmost of the classic muscarinic antagonists (e.g. atropine, hyoscine) are non-selective, pirenzepine is selective for M1receptors, and darifenacin for M2 receptors. Gallamine, better known as a neuromuscular-blocking drug, is also a selective, although weak, M2 receptor antagonist.

Recently, toxins from the venom of the green mamba have been discovered to be highly selective mAChR antagonists, as well as various synthetic compounds with some degree of selectivity.

Characteristics of Muscarinic Acetylcholine Receptor Subtypes (mAChRs)

Nicotinic receptorsThese receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. They are rosette-like pentameric structures. which enclose a ligand gated cation channel: their activation causes opening of the channel and rapid flow of cations resulting in depolarization and an action potential.

Nicotinic receptors are located centrally, in autonomic ganglia and in the neuromuscular junction of skeletal muscles.

The receptors exist at the skeletal neuromuscular junction, autonomic ganglia, adrenal medulla, the CNS and in non-neuronal tissues. The nAChRs are composed of five homologous subunits organized around a central pore.

In general, the nAChRs are further divided into two groups;

Muscle type, found in vertebrate skeletal muscle, where they mediate transmission at the neuromuscular junction (NMJ).

Neuronal type, found mainly throughout the peripheral nervous system, central nervous system, and also non-neuronal tissues

Nicotinic actionThe effects of stimulating these receptors are as follows:

• an increase in skeletal muscle tone;

• behavioural changes, including feelings of relaxation and wellbeing;

• increase in ‘autonomic tone’ above the resting state of activity of both parasympathetic and sympathetic effectors;

• release of adrenaline and noradrenaline from the adrenal medulla. this occurs because the adrenal medulla is, in reality, a modified autonomic ganglion.

Common adverse effectsThe effects of stimulating nicotinic receptors, both wanted and unwanted, are shown in Figures A and B.

Adverse effects include cardiovascular stimulation, headache, nausea and insomnia. Nicotine patches can cause skin reactions such as itching, burning and redness.

Figure A The effects of nicotinic receptor agonists

Figure B Flowchart showing the effects of nicotinic receptor agonists

Table for Characteristics of Subtypes of Nicotinic Acetylcholine Receptors (nAChRs)