Involvement of P2Y12 receptors in a nitroglycerin-induced model of migraine in male mice

Abstract

Background and purpose: P2Y₁₂ receptors regulate different forms of pain and inflammation. In this study, we investigated the participation of P2Y₁₂ receptors in an animal model of migraine.

Experimental approach: We tested the effect of the centrally administered selective P2Y₁₂ antagonist PSB-0739 and P2Y₁₂ receptor gene (P2ry12^-/- ) deficiency in acute nitroglycerin-treated mice. Additionally, platelet depletion was used to investigate the role of platelet P2Y₁₂ 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 P2Y₁₂ 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 P2Y₁₂ receptors alleviates migraine-like pain in mice by modulating the expression of c-fos and that platelet P2Y₁₂ receptors might contribute to this effect. Thus the blockade of P2Y₁₂ receptors may have therapeutic potential against migraine.

Keywords: P2Y12 receptor; PSB-0739; clopidogrel; migraine; mouse model; nitroglycerin.