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

were strong contenders for mediating the vasodilatation following
the initial vasospasm and subsequent hypoxia. ATP was also
implicated in the pathogenesis of pain during migraine via
stimulation of primary afferent nerve terminals located in the
cerebral vasculature. Recent studies have shown that the ATP-
induced cerebral vasodilatation is endothelium-dependent via
activation of P2Y-purinoceptors on the endothelial cell surface
and subsequent release of endothelium-derived relaxing factor
(EDRF); and that the endothelial cells are the main local source
of ATP involved, although ADP and ATP released from aggregating
platelets may also contribute to this vasodilatation. These findings
have extended the «purinergic» hypothesis for migraine in two
ways. Firstly, they have clarified the mechanism of purinergic
vasodilatation during the headache phase of migraine. Secondly, they
suggest that a purinergic mechanism may also be involved in the
initial local vasospasm, via P2X-purinoceptors on smooth muscle
cells occupied by ATP released either as a cotransmitter with
noradrenaline from perivascular sympathetic nerves or from
damaged endothelial cells. The hypothesis has gained further support
by the identification of P2X3 receptors on primary afferent nerve
terminals arising from trigeminal, nodose and spinal ganglia (12).
Thus, P2X3 receptor antagonists may be candidates for antimigraine
drug development (16). There is also recent evidence that migraine
is a chronic sympathetic nervous system disorder, where there is an
increase in release of sympathetic cotransmitters, including ATP,
which may contribute to the initial vasospasm.

MUSCULOSKELETAL SYSTEM

Several reports implicate purinergic signalling in bone
development and remodelling. P2X and P2Y receptors are present
on osteoclasts, osteoblasts and chondrocytes (17). ATP, but not
adenosine, stimulates the formation of osteoclasts and their
resorptive actions in vitro, and can inhibit osteoblast-dependent bone
formation. The bisphosphonate clodronate, which is used in the
treatment of Paget’s disease and tumour-induced osteolysis, may act
through osteoclast P2 receptors. Very low (nM) concentrations of
ADP acting through P2Y1 receptors turn on osteoclast activity.

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