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

Abstract

Background P2Y receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y 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 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y 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 P2Y 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, P2Y receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y receptors contribute to these effects in the chronic inflammation phase.

Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17

“…However, previous studies have not yet fully clari ed it mechanisms of action. Cangrelor is a second-generation P2Y12, and past studies have found that cangrelor alleviates the in ammatory response in lung brosis [21], chronic in ammatory pain [22], and neuropathic pain [23]. In the present study, we found that cangrelor decreased CLP-induced pulmonary injury by modulating the in ammatory response.…”

Microglia monitor and protect neuronal function through specialized somatic purinergic junctions

“…5D). To verify that PSB injected intra-cisterna magna only inhibited microglial P2Y12 receptors, and not those expressed by circulating platelets, we measured ADP-induced platelet activation in plasma samples 1 hour after MCAo, when blood-brain barrier injury is apparent (37,39,40). ADP-induced increases in platelet CD62P were not altered in mice treated with intra-cisterna magna PSB compared with vehicle-treated animals ( fig.…”

The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

“…Of interest due to the clinical availability of several selective antagonists (see below), a recent paper demonstrated that P2Y12 receptors expressed by platelets contribute to hyperalgesia and local inflammation in a chronic Complete Freund's Adjuvant (CFA)-induced inflammatory pain model in mice (Bekő et al, 2017). Authors demonstrated that P2Y12-/-mice developed milder signs of CFAinduced pain with respect to wild-type animals, in parallel with reduced signs of inflammation of the hind paw.…”

“…Although the concomitant activity on platelets could pose some safety problems, the evaluation of these drugs in different types of pain syndrome could therefore be accelerated by the availability of pharmacokinetics and pharmacodynamics data despite that the appropriate route of administration is identified to reach the CNS target on microglia cells. Interestingly in view of preclinical data showing a possible role for platelet P2Y12 receptors in the modulation of pain (see above; Bekő et al, 2017), genetic variability in the P2Y12 gene seems to contribute to individual differences in pain and opioid sensitivity. A recent study genotyped 31 single nucleotide polymorphisms (SNPs) throughout the P2Y12 gene and compared the different genotypes with pain severity in 90 cancer patients, and with a cohort of patients suffering from post-operative pain.…”