Study and Development of New Candidates for Anti-inflammatory and Antinociceptive Drugs that Inhibit the P2X7 Receptor

Introduction: Inflammation involves mediators that aim to remove stimuli and initiate tissue recovery. The P2X7 receptor plays a key role in inflammation and pain. ATP binding to this receptor releases cytokines like IL-1b, IL-6, and TNF-a, promoting inflammation. P2X7 receptor involvement is reported in many inflammatory diseases, and its inhibition is promising due to adverse effects of current treatments. Thus, new selective P2X7 inhibitors with high potency in humans are needed. Methods: We evaluated two synthetic substances on acute and chronic inflammatory pain models in Swiss Webster mice. In the 2.5% formalin-induced hyperalgesia model, PMM 75-17 and PMM 100-17 were administered at 0.1, 1, and 10 mg/kg 1 hour before intraplantar stimulation. We recorded the time spent licking the injected paw. In the CFA model, mice were injected in the hind paw, and mechanical allodynia was evaluated using von Frey filaments for 14 days. Daily treatments with vehicle or substances at 1 and 10 mg/kg were administered. On day 15, tissue was collected for analysis. We also evaluated the substances' effects on PSNL-induced neuropathic pain. One-third of the sciatic nerve was ligated, and five days post-surgery, animals received daily treatment of 1 or 10 mg/kg up to day 15. Pain was assessed using von Frey filaments and the Hargreaves test. Results: In the formalin model, substances significantly inhibited pain-related behavior at 1 and 10 mg/kg. PMM 75-17 showed 60% antinociceptive response at 1 and 10 mg/kg. PMM 75-17 and PMM 100-17 improved mechanical allodynia and edema in CFA-treated mice. In neuropathic pain-induced mice, PMM 75-17 at 1 or 10 mg/kg reverted mechanical and thermal sensitization. Conclusion: P2X7R antagonist candidates decreased hyperalgesia in acute and subchronic inflammation models and improved thermal sensitivity in neuropathic pain-induced mice, showing promising anti-inflammatory and antinociceptive effects.