Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice

•Acute simvastatin attenuated the morphine antinociceptive tolerance and withdrawal signs in morphine-dependent mice through NO pathway.•Chronic simvastatin attenuated the morphine antinociceptive tolerance and withdrawal signs in morphine-dependent mice through NO pathway.•Chronic simvastatin reduced NO and MDA, and increased total thiol and GPx in cerebral cortex of morphine-dependent mice through NO pathway.•Chronic simvastatin reduced NO and MDA, and increased total thiol and GPx in hippocampus of morphine-dependent mice through NO pathway. Oxidative stress and the nitric oxide (NO) pathway are involved in the development of opioid analgesic tolerance and dependence. Simvastatin modulates NO and oxidative stress, so the present study aimed to investigate its effect on the development and expression of morphine analgesic tolerance and withdrawal signs in mice. Morphine tolerance and dependence were induced by twice daily morphine injection (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was assessed by the hot-plate test and dependence by naloxone challenge, on the sixth day. To determine if the NO is involved in the effects of simvastatin, mice were pre-treated with l-arginine (200 mg/kg) or the NO synthesis inhibitors (L-NAME; 30 mg/kg) along with simvastatin (300 mg/kg). The results showed that acute and chronic administration of simvastatin reversed the antinociceptive tolerance of morphine and attenuated withdrawal signs in morphine-dependent mice, and this effect is reversed by l-arginine and augmented by l-NAME. Also, the concentration of NO and oxidative stress factors such as malondialdehyde content, total thiol, and glutathione peroxidase (GPx) activity in brain tissues was evaluated. Chronic administration of simvastatin reduced NO and malondialdehyde, and increased total thiol and GPx levels in the cerebral cortex and hippocampus of morphine-dependent mice which were antagonized by l-arginine, and augmented by l-NAME. In summary, simvastatin attenuates morphine-induced antinociceptive tolerance and withdrawal symptoms, at least partly, through antioxidative properties and nitric oxide pathway.