In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of
inflammatory and neuropathic pain and in acute thermal nociception. In correlation
with their activity to block the recombinant human P2Y12R, the majority of P2Y12R
antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar
CFA injection, and after partial ligation of the sciatic nerve in rats. They also
caused an increase in thermal nociceptive threshold in the hot plate test. Among the
six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor
antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and
IL-1beta protein were time-dependently overexpressed in the rat hind paw and lumbar
spinal cord following intraplantar CFA injection. This was accompanied by the upregulation
of TNF-alpha, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3mg/kg i.t.) attenuated
CFA-induced expression of cytokines in the hind paw and of IL-1beta in the spinal
cord. Subdiaphragmatic vagotomy and the alpha7 nicotinic acetylcholine receptor antagonist
MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine
induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect
the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination
and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect
of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain
models, on acute thermal nociception and on the induction of spinal IL-1beta. Here
we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic
effect of P2Y12R antagonism could be mediated by the inhibition of both central and
peripheral cytokine production and involves alpha7-receptor mediated efferent pathways.
