Dr.

Maria M Buckley

Neuropharmacology of the Dept of Pharmacology &

Therapeutics
Enteric Nervous System maria.buckley@ucc.ie
The Second Brain
Jacqueline Boone, The New
York Times Book Review
In ,"The Second Brain, Gershon
makes a persuasive,
impassioned and, at times,
downright lyrical case...the
book succeeds in presenting an
often grim and complex topic
in a surprisingly witty and
engaging manner"
 The Enteric Nervous System (ENS)

➢ Is considered a separate branch of the ANS to the sympathetic and parasympathetic branches

➢ Can independently control gut function although it is normally modified by extrinsic nerves

➢ Exhibits simple programmed functions (e.g., peristalsis)

➢ Contains multiple neurotransmitters

Comparing the PNS to the ENS

The difference
= Integration!
 ➢Normal gut function is essential for life

➢Motility, secretion, absorption,

digestion, defense
Why study the
ENS ➢The ENS co-ordinates and regulates
these activities

➢Defects in ENS implicated in functional

bowel disorders
The complexity &
anatomy of the ENS
The complexity
& anatomy of
the ENS

Goyal RK, Hirano I, New Engl J Med. 1996; 334:1106

 Signal transmission in
the ENS
• Presynaptic inhibition
• ACh, histamine, 5-HT, norepinephrine and neuropeptide Y

• Excitatory postsynaptic potential

• ACh, CCK, CGRP, 5-HT, histamine, interleukins, PACAP,
tumour necrosing factor a, and VIP

• Inhibitory postsynaptic potential

• Adenosine, ATP, CCK, 5-HT,
• norepinephrine, opioids,
• and somatostatin
 Submucosal versus myenteric ganglia

Myenteric Plexus Submucosal plexus

➢Regulates motility ➢Regulates secretion and blood flow

➢Contains afferent neurons, ➢Contains afferent neurons and motor

interneurons and motor neurons neurons

➢Large (up to 200 neurons) ganglia ➢Smaller (up to 30 neurons) ganglia

Significant interaction
The law of the intestine (peristaltic reflex)

Stimulus
Oral Anal

Contraction Relaxation
The law of the intestine (peristaltic reflex)
Cholinergic fast synaptic pathways
Non-cholinergic fast excitatory synaptic pathways
Slow excitatory synaptic pathways
Serotonin (5HT) is an important activator of
gastrointestinal nerves
❑ 95% of the body’s serotonin is located in
the bowel, and most 5HT in the bowel is
synthesized by enterochromaffin (EC)
cells.
❑ 5HT released from EC cells can initiate
reflex responses such as intestinal
secretion and peristalsis, and when
released in large amounts, it causes
nausea and vomiting.
❑ The actions of 5HT are terminated by
reuptake involving the same
serotonin-selective transporter
(SERT) that is found in the CNS.
Intrinsic reflex circuits that control motility involve enteroendocrine and neuronal
signaling

Oral Anal
Longitudinal muscle
Myenteric plexus
Circular muscle

Submucosal plexus

Mucosa
EEC

Pressure Gradient
 ➢Different to skeletal muscle neuromuscular
junction – no motor end plates.

➢Neurotransmitters must diffuse for ~ 100

nm
Enteric
neuromuscular ➢Closer contacts between interstitial cells of
Cajal (ICCs) and smooth muscle cells (SMC)
transmission and between ICC and nerve terminals (NT)

➢Cajal (1911) proposed that ICCs mediate

neurotransmission between NT and SMC
Enteric motor transmission
 Two types

➢Cholinergic (ChAT/NPY and Chat/Calretinin)

- 33% of SMP Project to mucosa and
Enteric some (calretinin-IR) to submucosal
arterioles
secretomotor
neurons ➢Non Cholinergic (VIP)
- 43% of the SMP
- Project to the mucosa and submucosal
arterioles
 Secretion

Submucosal reflex
➢ Afferent and efferent branches confined to submucosa

➢ Coordination of motility and secretion

➢ - Myenteric IPANs and interneurons project to the submucosal plexus
➢ - Some secretomotor neurons reside in the myenteric plexus
Neural control of mucosal ion transport
• Enteric secretomotor neurons stimulate epithelial secretion of Cl- &
H20

• Sympathetic neurons inhibit enteric neurons and can also activate α2

receptors on mucosal epithelium, causing absorption.
Intrinsic reflex circuits also control fluid and electrolyte movement

Oral Anal
Longitudinal muscle
Myenteric plexus
Circular muscle

Submucosal plexus

Mucosa

Activation of
Cl- epithelial
Cl- H2O secretion
Cl-
 Anti-diarrhoeal: Mu opioid agonists
Codeine, loperamide
Loperamide
Morphine

❑Adverse effects
-may cause respiratory depression in babies or small children
-paralytic ileus in patients with active IBD
De Luca and Coupar, 1996
Anti-diarrhoeal: Mu opioid agonists
Codeine, loperamide
Inflammation or infection

H20 Cl- Cl-

H20 H20 Cl-
CFTR
↑cAMP ↑cAMP
↑cAMP
↑cAMP ↑cAMP
↑cAMP

NPY/Somatostatin
Loperamide

“Anti-secretory nerve”
Mu opoid receptor 5HT
Opioid-induced bowel dysfunction

• Morphine and related opioid analgesics are the mainstay of therapy

in many patients with moderate to severe pain:

• - A delay in GI transit and constipation

• Incomplete evacuation, abdominal distension, bloating, abdominal

discomfort and increased gastro-oesophageal reflux

• Opiate blockade of gut motility correlates with opiate concentrations

in the ENS than with opiate concentrations in the CNS
Opioid-induced bowel dysfunction: peripheral μ-opioid receptor
antagonists in the CNS and gastrointestinal tract
Irritable bowel
syndrome Psychosocial Altered Motility
(IBS) Factors Distention
Neurotransmitter, Spasm
imbalance?,
Infection and,
inflammation?

Visceral Hypersensitivity
Pain,
Bloating,
Urge to defecate
Brain-gut interactions in response to stress
 Effects of 5HT3 receptor antagonists and 5HT4 receptor agonists on
enteric-nerve mediated gut function

Neurones
Muscle motor Sensory Secretomotor Clinical impact
5-HT3 antagonist ↓ Peristalsis ↓
Motility
5-HT4 agonist ↑ Peristalsis ↑

5-HT3 antagonist ↓ Nociception ↓

Visceral
Compliance ↑
sensitivity 5-HT4 agonist
Nociception ↓

Mucosa 5-HT3 antagonist ↓ Peristalsis ↓

5-HT4 agonist ↑ Peristalsis ↑
 Model of 5HT3 and
5HT4 receptor pathways
in the enteric nervous
system

• Talley NJ, Lancet 2001; 358: 2061–68

 Serotonergic agents and the irritable bowel syndrome (IBS): what goes
wrong?
❑5HT3 antagonist; i.e. alosetron
- Clinically beneficial in treating diarrhoea and abdominal pain
- Serious side effect; ischemic colitis
- Inhibition of 5HT-induced vasodilatation?
- Physical factors; stool pressure on mucosa?
❑5HT4 agonist; i.e. tegaserod
- Increased thrombotic risk
- Mechanism for this side effect is unclear
- Future uncertain

❑5-HT4 agonist/5-HT3 antagonist; i.e. renzapride

- “Headline results from the Phase III study in April 2008 showed
renzapride to be safe and well tolerated, but demonstrated limited
efficacy. As a consequence, Alizyme has discontinued all further
investment in the clinical development of renzapride.”
http://www.alizyme.com/alizyme/products/renzapride/
Spiller R, Curr Opin Pharmacol. 2008 Dec;8(6):709-14.
 Glutamate and Glu
receptors in the
enteric nervous
system; novel
therapeutic targets?

Kirchgessner AL, Current Opinion in Pharmacology 2001, 1:591–596

 ➢ Glutamate (Glu)-immunoreactive neurons are
located in the
➢ submucosal plexus and myenteric plexus and
display both ChAT and SP immunoreactivity.
Glutamate and Glu
receptors in the ➢ Glutamatergic submucosal neurons are
enteric nervous presumed to be primary afferent neurons that
project axons to the mucosa and can detect
system; novel mucosal stimuli (e.g. chemical and mechanical
stimuli).
therapeutic targets?
➢ Extrinsic primary afferent neurons are found in
the nodose and dorsal root ganglia and
transmit sensory information to the CNS.
Enteric mGlu receptors present potential new target
sites for the development of gastrointestinal drugs; however,
a problem associated with studying their physiological
function is the lack of selective agonists and antagonists.