PHAR0004/9/7 - General and Systematic Pharmacology/

Intermediate Pharmacology/Introductory Pharmacology

THE PERIPHERAL NERVOUS SYSTEM Professor A. H. Dickenson

The peripheral nervous system comprises all CNS output except the somatic (motor) fibres. It is not
usually controlled by the CNS and acts to control the internal bodily environment. The peripheral
nervous system (autonomic nervous system) is an effector system and controls (1) heart beat
(chronotropic and inotropic) (2) contraction and relaxation of smooth muscle (3) all exocrine function
(4) some endocrine function (5) some steps in intermediate metabolism.

AUTONOMIC NERVOUS SYSTEM

1. ANATOMY AND ORGANISATION

The autonomic nervous system (ANS) is characterised by having 2 neurones outside the central nervous
system (CNS). Preganglionic nerves arising from the CNS synapse on the cell body of the
postganglionic neurones in the ganglia. The postganglionic neurones (carried in either nerve bundles or
plexi) terminate at the effector cell. Preganglionic fibres are myelinated B fibres. Postganglionic fibres
are non-myelinated C fibres.

There are three divisions of the ANS. The distinction is primarily anatomical. The sympathetic and
parasympathetic nervous system have opposing actions in some, but not all situations.

I. Parasympathetic (cranial-sacral) nervous system (PNS)

Output from the mid-brain, medulla (leave with cranial nerves III, VII, IX, X) and sacral part
of the spinal cord. The parasympathetic ganglia are near to or in the innervated tissues.

II. Sympathetic (thoracic-lumbar) nervous system (SNS)

Output (T1-12, L1-3) leaves with spinal nerves and synapse in ganglia either side of the
vertebral column (sympathetic chain). The ganglia are distal to the innervated tissue.

III. Enteric nervous system

In addition to the PNS and SNS, the enteric nervous system innervates the gastrointestinal
tract, pancreas and gall bladder. Local sensory neurones respond to muscle tension and
chemical stimulation and control function via motoneurones. The enteric nervous system can
function autonomously but is also controlled by PNS and SNS via an extrinsic innervation.

2. TRANSMITTERS

Acetylcholine is the transmitter released from all preganglionic neurones of bot parasympathetic
and sympathetic nerves (including the preganglionic fibres to the adrenal medulla) and from all
postganglionic parasympathetic neurones. Cholinergic transmission.

Noradrenaline is the transmitter released from most postganglionic sympathetic neurones.

Adrenergic (noradrenergic) transmission.

Exceptions are (1) Cholinergic postganglionic sympathetic neurones innervating sweat glands of the
skin (2) Adrenal medullary cells. The adrenal medulla is a "modified ganglion", shows nicotinic N1
responses.

The intrinsic enteric neurones, contained in plexuses use a number of transmitters including 5HT, purines
and peptides (substance P, enkephalins, CCK, VIP etc).

Department of Neuroscience, Physiology and Pharmacology, UCL

 A. ACh in Autonomic Ganglia and the Parasympathetic Nervous System

Synthesis, storage, secretion and inactivation of acetylcholine (ACh) are essentially the same as in the
neuromuscular junction (NMJ). The main differences between the pharmacology of cholinergic
neurones terminating at the NMJ and those which synapse in autonomic ganglia and the parasympathetic
nervous system are the anatomical organisation and differences in receptors.

The function of ganglia is to integrate and amplify information input. In sympathetic ganglion the ratio
of pre- to post-ganglionic fibres is about 1:20. More than one preganglionic neurone may synapse on a
single post-ganglionic fibre. In most parasympathetically innervated organs the pre to post-ganglionic
ratio is 1:1 (except in the gut where the ratio can be as high as 1:8000).

Preysnaptic modulation: ACh release is regulated presynaptically by ACh (M2, inhibitory).

B. NA in the Sympathetic Nervous System

All (except sweat gland innervation) postganglionic sympathetic fibres release noradrenaline which then
acts on  and  receptors.

Presynaptic modulation of NA release

Inhibitory via NA(2), Auto-inhibitory feedback reduces amount of NA released. Via inhibition of
adenylate cyclase, reduction of Ca++ entry.
Also via ACh muscarinic opiates (), histamine (H2), adenosine (P1), Dopamine (D2), prostaglandin E.
All inhibitory.

C. Co-transmission (Pre- or synaptic modulaton – Neuromodulation)

Note Dale's Principle. Co-transmission in ganglia can be manifest as a slow excitatory effect (LHRH,
causes reduction in K+ permeability) or an inhibitory effect (Opiates and muscarinic receptors, cause an
increase in K+ permeability).

D. Non-adrenergic Non-cholinergic (NANC) Transmission at Target Sites

Not all post-ganglionic autonomic transmission can be explained by NA or ACh. There is often a
residual action which can be due to one or more other effectors. This is known as NANC transmission.
NANC can be excitatory (ATP and Substance P) or inhibitory (neurotensin,VIP). Action of NANC is
also tissue-dependent (excitatory in vas deferens, blood vessels, inhibitory in the gut). Known NANC
transmitters include.

(i) Classical transmitters DA (sympathetic neurones, kidney), GABA (enteric neurones), 5-

HT (enteric neurones).

(ii) Purinergic transmission. Uses ATP as the transmitter. (Post ganglionic sympathetic neurones e.g.
blood vessels, vas deferens) Best characterised. Now considered to be a "classical" transmitter.
Responsible for the fast excitatory post-synaptc potential and rapid phase of contraction produced
by sympathetic nerve activity in many smooth muscle tissues. Subclassification of receptors into
P1 and P2. These subtypes have been themselves subclassified.
(iii) Peptide transmitters VIP, NPY, LHRH, prostaglandins, Substance P, CGRP, ANP,
histamine, NO, Endothelin

(iv) Nitric Oxide (NO)

Nitric oxide is a short-lived gas which nevertheless acts akin to a transmitter. NO mediates relaxation
of the stomach induced by vagal (PNS) stimulation and relaxation of other muscle from intrinsic NANC
nerves. In addition, the vasodilator effects of ACh, bradykinin etc. are also via NO. The mechanism of
action is via an increase in cGMP.