Evaluation the effect of chronic administration of Marrubium vulgare on the development of tolerance to morphine analgesia in male rats

Abstract

Introduction: Increase of pain-relieving tolerance and withdrawal syndrome of opioids have limited their usage. Chronic administration of morphine causes stimulation of glial cells activity and increases production of pro-inflammatory mediators such as TNFα, interleukins and products of cyclooxygenase activity, which is one of the reasons of tolerance to the analgesic effects of morphine. Due to analgesic and anti-inflammatory properties of Marrubium vulgare and its inhibitory effect on of the COX enzyme, it is expected that it can delay tolerance to morphine. Objective: The main purpose of this study was to evaluate the effects of Marrubium vulgare on reducing tolerance to morphine analgesia. Method: 500 grams of M. vulgare was extracted with methanol through maceration process. To evaluate morphine dependence, rats were assigned to 6 groups (n=8) that received morphine (10 mg/kg), morphine with three different doses of the extract (20, 40 and 80 mg/kg), morphine with the vehicle (0.25 ml/rat DMSO 50% in saline) and the group that received just the extract. Every other day after half an hour from the injections, hotplate tests were carried out for each group till TL equaled BL. It should be mentioned that when TL equals BL, tolerance is achieved. Results: Tolerance was induced in morphine group in day 7. Compared with morphine group, the groups receiving the extract with doses of 20, 40 and 80 mg/kg demonstrated tolerance in day 9, 11 and 19, respectively. The AUC of these groups showed a significant difference with the morphine group with p<0.01, p<0.001 and p<0.001, respectively. Conclusion: Our results suggested that methanolic extract of M. vulgare can significantly delay tolerance to morphine. This result raised the hope of obtaining a substance which could postpone clinical difficulties associated with long term use of opioids.