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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

for the drug treatment of irritable bowel syndrome (11). Bile induces
ATP depletion and contributes to the early mucosal permeability
alteration and barrier lesions that occur during experimental
oesophageal reflux. P2X3 immunohistochemistry has been
demonstrated in aganglionic bowel in Hirschsprung’s disease,
suggesting that the sensory nerves may form a significant proportion
of its hypertrophic innervation. P2Y receptors in smooth muscle and
ATP production in myenteric neurons increase in postoperative ileus,
probably contributing to delayed colonic transit. An inhibitor of
purinergic transmission, OrphaninFG, reversed postoperative ileus
in rats and therefore may have therapeutic application. Recent
reviews have highlighted the potential of purinergic drugs for the
treatment of functional bowel disorders and visceral pain (11).

Intrinsic sensory neurones in the submucous plexus of the gut,
as well as extrinsic sensory nerves, show positive immunoreactivity
for P2X3. It has been proposed (12) that during moderate
distension, low threshold intrinsic enteric sensory fibres may be
activated via P2X3 receptors by ATP released from mucosal
epithelial cells, leading to reflexes concerned with propulsion of
material down the gut. Studies showing that peristalsis is impaired
in the small intestine of mice lacking the P2X3 subunit support this
view. In contrast, during substantial (colic) distension associated
with pain, higher threshold extrinsic sensory fibres may be
activated by ATP released from the mucosal epithelia; these fibres
pass messages through the dorsal root ganglia to pain centres in
the central nervous system (10).

In the liver, purinergic receptors have been identified in the
plasma membrane of the two principal epithelial cell types that form
the bile secreting unit, namely hepatocytes, which constitute the
liver parenchymal cells and cholangiocytes, which line the lumen of
intrahepatic bile ducts. Activation of the receptors has been linked to
several fundamental responses important to cellular metabolism, ion
channel activation, cell volume regulation and bile formation. It is
suggested that pharmacological modulation of ATP release and
purinergic signalling might provide novel strategies for the
management of cholestasis and other disorders characterised by
impaired bile flow. Purinergic receptors are present on both
quiescent and activated hepatic stellate cells; quiescent cells express

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