Involvement of P2Y 12 receptors in a nitroglycerin‐induced model of migraine in male mice

Background and purpose: P2Y12 receptors (P2Y12 Rs) are known to regulate different forms of pain and inflammation. In this study we investigated the participation of P2Y12 Rs in an animal model of migraine. Experimental approach: We tested the effect of the centrally administered selective P2Y12 R antagonist PSB-0739, and P2Y12 R gene deficiency in acute nitroglycerin (NTG)-treated mice. Additionally, platelet depletion was used to investigate the role of platelet P2Y12 Rs during migraine-like pain. Key results: NTG 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 (TNC). Similar changes were also observed in P2Y12 R 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, it was also effective when applied as a post-treatment. PSB-0739 administration suppressed the expression of c-fos in C1-C2 and TNC, and decrease C1-C2 levels of dopamine and serotonin in wild-type mice. NTG treatment itself did not change adenosine diphosphate (ADP)-induced platelet activation measured by CD62P upregulation in wild-type mice. Platelet depletion by anti-mouse CD41 antibody and clopidogrel attenuated NTG-induced thermal hypersensitivity and head grooming time in mice. Conclusion and implications: Taken together, our findings show that acute inhibition of P2Y12 Rs alleviates migraine-like pain in mice, by modulating the expression of c-fos, and platelet P2Y12 Rs might contribute to this effect. Hence, it is suggested that the blockade of P2Y12 Rs may have therapeutic potential against migraine.