Involvement of P2Y(12) receptors in a nitroglycerin-induced model of migraine in male mice

Background and Purpose P2Y(12) receptors regulate different forms of pain and inflammation. In this study, we investigated the participation of P2Y(12) receptors in an animal model of migraine. Experimental Approach We tested the effect of the centrally administered selective P2Y(12) antagonist PSB-0739 and P2Y(12) receptor gene (P2ry12(-/-)) deficiency in acute nitroglycerin-treated mice. Additionally, platelet depletion was used to investigate the role of platelet P2Y(12) receptors during migraine-like pain. Key Results Nitroglycerin induced sensory hypersensitivity of C57BL/6 wild-type (P2ry12(+/+)) mice accompanied by an increase in c-fos and CGRP expression in the upper cervical spinal cord (C1-C2) and trigeminal nucleus caudalis. Similar changes were also observed in P2Y(12) gene-deficient (P2ry12(-/-)) mice. Prophylactic intrathecal application of PSB-0739 reversed thermal hyperalgesia and head grooming time in wild-type mice but had no effect in P2ry12(-/-) mice. Furthermore, PSB-0739 was also effective when applied as a post-treatment. PSB-0739 administration suppressed the expression of c-fos in C1-C2 and trigeminal nucleus caudalis, and decreased the levels of dopamine and 5-hydroxytryptamine in C1-C2 in wild-type mice. Nitroglycerin treatment itself did not change adenosine diphosphate (ADP)-induced platelet activation measured by CD62P up-regulation in wild-type mice. Platelet depletion by anti-mouse CD41 antibody and clopidogrel attenuated nitroglycerin-induced thermal hypersensitivity and head grooming time in mice. Conclusion and Implications Our findings show that acute inhibition of P2Y(12) receptors alleviates migraine-like pain in mice by modulating the expression of c-fos and that platelet P2Y(12) receptors might contribute to this effect. Thus the blockade of P2Y(12) receptors may have therapeutic potential against migraine.