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

the cotransmission of ATP with g-aminobutyric acid in retinal
nerves, and with glutamate, 5-hydroxytryptamine (serotonin), NA
or dopamine in nerves in the brain. In sympathetically innervated
tissues, such as the vas deferens or blood vessels, ATP produces
fast responses mediated by P2X receptors, followed by a slower
component mediated by G protein-coupled a-adrenoceptors.
Similarly, in the parasympathetic nerves supplying the urinary
bladder, ATP provokes a fast transient resonse via P2X receptors,
while the slower component is mediated by G protein-coupled
muscarinic receptors. There are differences in the proportion of
cotransmitters between species and in different pathophysiological
conditions. P2X3 receptors are selectively localised on sensory neurons
in trigeminal, nodose and dorsal root ganglia (DRG), and the
terminals of these nociceptive neurons in the skin and visceral organs
represent unique targets for novel analgesic agents that function as
P2X3 receptor antagonists. Non-specific P2 receptor antagonists, eg
suramin, are antinociceptive, and P2X3 receptor-knockout mice have
reduced nociceptive inflammatory responses (12). The first clear
evidence for nerve-nerve purinergic synaptic transmission was
published in two papers in Nature in 1992. Synaptic potentials in the
coeliac ganglion and in the medial habenula in the brain were
reversibly antagonised by suramin, a P2X antagonist. Since then,
many articles have described either the distribution of various P2
receptor subtypes in the brain and spinal cord or electro-physiological
studies of the effects of purines in brain slices, isolated nerves and
glial cells (23). Synaptic transmission has also been found in the
myenteric plexus and in various sensory, sympathetic and pelvic
ganglia. Adenosine, produced by the ectoenzymatic breakdown of
ATP, acts through presynaptic P1 receptors to inhibit the release of
excitatory neurotransmitters in both the peripheral and the central
nervous systems. P2Y receptors are expressed on both nonmyelinating
and myelinating Schwann cells.

In the brain, purinergic signalling is involved in the regulation of
a variety of physiological and pathophysiological processes, including
development and nervous tissue remodelling following trauma,
stroke, ischaemia or neurodegenerative disorders (23). Agonists and
antagonists of adenosine and ATP are being explored as therapeutic
agents for a number of neurological conditions. For example,

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