Pharmacological evidence for systemic and peripheral antinociceptive activities of pioglitazone in the rat formalin test: Role of PPARγ and nitric oxide

Nitric oxide (NO) is involved in numerous physiological processes of the central and peripheral nervous system. This study aimed to evaluate the involvement of PPARγ and NO pathway in the systemic and peripheral antinociceptive effect pioglitazone (Pio) using formalin test in rats. After allocation, rats were injected with 2.5% formalin solution and the flinching behaviors were recorded for 5 min (phase 1) and 15-60 min (phase 2). Pioglitazone was administered intraperitoneally (i.p.) at doses (10-50 mg/kg) and intraplantarly (i.pl.) at doses (10-30 μg/paw) 60 and 20 min before test, respectively. To investigate the mechanism involved, rats were given GW-9662 (a PPARγ antagonist), L-NAME (NO synthase inhibitor), L-arginine (NO precursor), or l-NAME+GW-9662 along with pioglitazone. Results showed that both of i.p. and i.pl. routes of pioglitazone administration produced antinociception in both phases of formalin-induced pain. Antinociception caused by i.p. and i.pl. pioglitazone was blocked by GW-9662 at doses 2 mg/kg (i.p.) and 3 μg/paw (i.pl.) in both phases of the test, respectively. The antinociceptive effects of i.p. and i.pl. pioglitazone were significantly reduced by l-arginine, but were augmented by l-NAME in second phase of test. However, pre-treatment with GW-9662 inhibited the enhanced antinociceptive effect of l-NAME on pioglitazone in second phase of formalin test during i.p. and i.pl. administration. Furthermore, the antinociceptive effect of systemic pioglitazone was antagonized by i.pl. administration of GW-9662 (3 μg/paw). Our data suggest that local and systemic antinociceptive activity of pioglitazone is mediated partly through PPARγ in collaboration with NO pathway. Moreover, the cumulative results suggest a close link of interaction between PPARγ and NO.