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

Background: P2Y(12) receptor antagonists are widely used in clinical practice to inhibit platelet aggregation P2Y(12) receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y(12) receptors contribute to these effects. Objectives: To explore the contribution of platelet P2Y(12) receptors to chronic inflammatory pain in mice. Methods: Complete Freund's adjuvant (CFA)- induced chronic inflammatory pain was induced in wild- type and P2ry(12) 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 P2ry(12) (-/-) mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)- a and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)- 1b, IL- 6, TNF- a and KC levels were attenuated in P2ry(12) (-/-) mice. PSB- 0739 and cangrelor reversed hyperalgesia in wild- type mice but had no effect in P2ry(12) (-/)- 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 P2ry(12) (-/-) mice on day 14. Conclusions: In conclusion, P2Y(12) receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y(12) receptors contribute to these effects in the chronic inflammation phase.