Evaluation of the effects of ketotifen and methanolic extract from aerial parts of Artemisia marschalliana on the morphine withdrawal syndrome in mice

Abstract

Introduction: Different neurotransmitter systems (glutaminergic, adrenergic and histaminergic, etc.), oxidative stress, and the increase of inflammatory factors affect the opioid system and involved in morphine dependence. Ketotifen has inhibitory effects on the NMDA system and Artemisia marschalliana extract (Anti-malarial, anti-flatulence, anti-cough, …) has inhibitory effects on oxidative stress. Aim: The aim of this study was the evaluation of the effects of ketotifen and methanolic extract from aerial parts of Artemisia marschalliana on the morphine induced withdrawal syndrome in mice. Method: 90 male mice in 10 groups of 9 in the weight range of 20-30 g were randomly selected and received the following drug regimens once a day for two weeks. 1) Saline (10ml/kg,ip) + Saline (10ml/kg,ip) 2) Saline (10ml/kg,ip) + Morphine (25mg/kg,ip) 3) DMSO 20% (10ml/kg,ip) + Morphine (25mg/kg,ip) 4-5-6) A.M.E (50,100,200mg/kg,ip) + Morphine (25mg/kg,ip) 7-8-9) Ketotifen (4,8,16mg/kg,ip) + Morphine (25mg/kg,ip) 10) A.M.E (50mg/kg,ip) + Ketotifen (4mg/kg,ip) + Morphine (25mg/kg,ip) On the fourteenth day, two hours after morphine injection, naloxone (4mg/kg,ip) was injected and withdrawal symptoms were measured within half an hour. Finally, to measure serum MDA and TAC levels in different groups, the animals were anesthetized and blood samples were taken from the heart. Result: The results showed that administration of ketotifen and Artemisia marschalliana extract or their combination in low doses before daily morphine injection reduced morphine dependence (P<0.01). No significant correlation was observed between serum MDA and TAC levels and withdrawal symptoms. Conclusion: Based on these results, the above drugs can be used to reduce morphine dependence. Possibly that ketotifen and methanolic A.marschalliana extract with the doses that have been examined in the present study, inhibit the dependence through a pathway other than the oxidative stress mechanism. Further studies are needed to be able to understand this matter.