The ameliorative effects of phenylmethylsulfonyl fluoride on morphine tolerance and dependence in mice

Introduction: Opioids use such as morphine has been limited due to tolerance and dependence as major unwanted effects of opioids. Previous evidence has shown that targeting endocannabinoid signaling can prevent the development of opioid tolerance and dependence. Accordingly, this study was designed to evaluate the effect of phenylmethylsulfonyl fluoride (PMSF) an inhibitor of fatty acid amide hydrolase (FAAH) on morphine antinociceptive tolerance and physical dependence in mice.Materials and Methods: The antinociceptive effects of PMSF at the doses 60, 120 and 300 mg/kg were investigated. The dose of (60 mg/kg, i.p.) of PMSF is defined as subeffective dose. Morphine tolerance and dependence were induced by twice daily injection of morphine (10 mg/kg, s.c.) for 10 consecutive days and the last dose on day 11. Tolerance was assessed by the hot-plate test and dependence by naloxone-precipitated morphine withdrawal signs including jumping and weight loss. In the brain, oxidative stress markers include activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase and levels of malondialdehyde (MDA) and glutathione (GSH) were determined.Results: These results showed that PMSF has notable antinociceptive effect at the doses 120 and 300 mg/kg. A sub-antinociceptive dose (60 mg/kg) of PMSF could reduce tolerance in both acute and chronic methods of administration. However, alleviation of dependence and suppression of oxidative stress markers occurred in the chronic administration of PMSF.Discussion and Conclusion: PMSF in chronic use with morphine can reduce the induction of tolerance and dependence. Acute co-administration of PMSF with morphine was accompanied with the alleviation of morphine tolerance but had no effect on dependence and oxidative stress. These effects of PMSF may be related to increases in endocannabinoid levels, and consequently contributing to the opioids system in the suppression of morphine tolerance and dependence.

کلیدواژه ها:

Morphine ، Tolerance ، Dependence ، Oxidative stress ، PMSF ، Mice