Anti-inflammatory and anti-hyperalgesic effect of all-trans retinoic acid in carrageenan- induced paw edema in Wistar rats: Involvement of peroxisome proliferator-activated receptor-β/δ receptors

Objective: In this study, we investigated the role of peroxisome proliferator-activated receptors (PPAR)-beta/delta receptors in carrageenan-induced inflammation and in the anti-inflammatory effects of all-trans retinoic acid (ATRA). Materials and Methods: The lambda-carrageenan (0.1 ml of 1% w/v) was injected into intra-plantar (i.pl.) region of the hind paw to produce acute inflammation. Paw volume was measured by using the mercury plethysmography. Further, mechanical and thermal hyperalgesia (TH) were assessed by using the dynamic plantar aesthesiometer and plantar test apparatus, respectively. In addition, markers of oxido-nitrosative stress were assessed spectrophotometrically in the hind paw tissue 5 h post-carrageenan. Results: An i.pl injection of carrageenan has produced a marked mechanical hyperalgesia (MH) and TH in ipsilateral paw, which was associated with significant elevated oxido-nitrosative stress. Treatment with ATRA (5 mg/kg/p.o/4 days) and GW0742, a selective PPAR-beta/delta receptor agonist (0.1 mg/kg/i.p/4 days), significantly decreased the paw volume, mechanical and TH as compared to vehicle control. Administration of GSK0660, selective PPAR-beta/delta receptor antagonist, at a dose of (0.3 mg/kg/i.p/4 days), did not produce a significant effect on carrageenan-induced paw edema, MH and TH. However, co-administration of GSK0660 (0.3 mg/kg/i.p/4 days) along with both ATRA (5 mg/kg/p.o/4 days) and GW0742 (0.1 mg/kg/i. p/4 days), significantly reverse the decreased paw edema, MH, and TH. These observed ameliorative effects on inflammatory pain symptoms are correlated with the extent of reduction of oxido-nitrosative stress. Conclusion: From above findings, it can be concluded that ATRA exerts anti-inflammatory and anti-hyperalgesic effect, possibly through activation of PPAR-beta/delta and subsequent reduction of oxido-nitrosative stress.