Role of PPARα and PPARγ in Mediating the Analgesic Properties of Ibuprofen in vivo and the Effects of Dual PPARα/γ Activation in Inflammatory Pain Model in the Rat

Background and Objective: Ibuprofen is commonly used to treat various inflammatory pain disorders. Its analgesic properties are attributed mainly to inhibiting cyclooxygenases enzymes and blocking the production of prostaglandins. The aim of this study is to evaluate the role of PPAR alpha and PPAR gamma in mediating the anti-nociceptive effects of ibuprofen in vivo. The anti-nociceptive effects of PPAR alpha and PPAR gamma dual activation are also investigated. Methodology: Hot plate analgesia meter and the von Frey filament test were used to evaluate the anti-hyperalgesic effects of ibuprofen on CFA inflammatory pain model in rat and the role played by PPAR alpha and PPAR gamma in mediating these effects. Behavioral tests were performed at two different time points (1 and 6 h) representing the slow and rapid-onset effects of ibuprofen. Results: Ibuprofen (100 mu g) significantly restored both the Paw Withdrawal Latency (PWL) and Paw Withdrawal Thresholds (PWT) after CFA injection at the 2 time points selected. Co-administration of the PPAR alpha antagonist GW6471 (50 mu g) or the PPAR gamma antagonist GW9662 (50 mu g) significantly reduced the anti-nociceptive effects of ibuprofen on PWT 1 h post-drug administration. However, co-administration of GW6471 but not GW9662 significantly reduced the inhibitory effects of ibuprofen on PWL 1 h post-drug administration. Co-administration of GW6471 or GW9662 significantly reduced the inhibitory effects of ibuprofen on both PWL and PWT at 6 h post-drug administration. The dual PPAR alpha/gamma agonist tesaglitazar (5 mu g) only reversed thermal PWL at 6 h post-drug administration. Conclusion: The PPAR alpha and PPAR gamma at least partially mediate the analgesic properties of ibuprofen. The dual activation of PPAR alpha/gamma receptors could provide a promising strategy to control chronic pain conditions characterized by thermal hyperalgesia.