This study aimed to determine the potential systemic and local anti-nociceptive effects of simvastatin (SIM) and the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide (NO) pathways using a formalin assay in rats. After allocation, rats were intraplantarly (i.pl.) treated with formalin solution (2.5%) and the flinching behaviors were recorded for 5 min (phase 1) and 15-60 min (phase 2). SIM was given intraperitoneally (i.p.) and i.pl. 30 and 20 min before test, respectively. Intraperitoneal administration of SIM attenuated the flinching number during both phases of the test. This effect of i.p. SIM was significantly reduced by L -NAME (NO synthase blocker, i.p.), but was augmented by L -arginine (NO precursor, i.p.) during both phases of the formalin assay. Moreover, the antinociception caused by i.p. SIM was blocked by GW-9662 (PPARγ antagonist) at dose 2 mg/kg (i.p.). In another experiment, concurrent ip administration of non-effective dose of simvastatin (5 mg/kg) with pioglitazone (PPARγ agonist; 10, 20 mg/kg) produced antinociception. However, pre-treatment with i.p. GW-9662 inhibited the enhanced antinociceptive effect of pioglitazone on SIM during the phase 2 of formalin assay. Results also showed that i.pl. SIM alone had no anti-nociceptive effects. However, significant anti-nociception was observed when SIM (i.pl.) co-administered with non-effective dose of pioglitazone. Moreover, the enhanced effect was antagonized by pre-treatment with i.pl. GW-9662. Our data suggest that SIM produced antinociception through systemic but not local route of administration in rats. Moreover, the antinociceptive effect of SIM is partly mediated through PPARγ receptors and NO pathway. © 2017 Wiley Periodicals, Inc.
Keywords: Antinociception; Formalin assay; Nitric oxide; PPARγ; Simvastatin.
© 2017 Wiley Periodicals, Inc.