Contribution of platelet P2Y₁₂ receptors to chronic Complete Freund's adjuvant-induced inflammatory pain

Essentials The role of platelet P2Y₁₂ receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y₁₂ receptors attenuate hyperalgesia and local inflammation. Platelet P2Y₁₂ receptors contribute to these effects in the chronic phase of inflammation.

Background P2Y₁₂ receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y₁₂ receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y₁₂ receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y₁₂ receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain was induced in wild-type and P2ry12 gene-deficient (P2ry12^-/- ) mice, and the potent, direct-acting and reversible P2Y₁₂ receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12^-/- mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-α and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1β, IL-6, TNF-α and KC levels were attenuated in P2ry12^-/- mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12^-/- mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12^-/- mice on day 14. Conclusions In conclusion, P2Y₁₂ receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y₁₂ receptors contribute to these effects in the chronic inflammation phase.