Investigation on the Effect of Ketotifen Upon Morphine Tolerance and Dependence in Mice

Abstract

Background: Morphine is one of the most common drugs for intense pain relief in a clinic, however, its chronic use and repeated administration leads to morphine tolerance and dependence. Objectives: In this study, effects of ketotifen as histamine H1 receptor antagonist and mast cell stabilizer have been investigated on the induction and expression of morphine tolerance and dependence in mice. Methods: At first, antinociceptive effects of ketotifen were measured using hot-plate test to find out the subeffective doses of ketotifen. Morphine tolerance and dependence was induced during a six day period with 11 doses of 10 mg/kg morphine, subcutaneously. Morphine tolerance was evaluated in hot plate model of antinociception. Morphine dependence was precipitated by naloxone 5 mg/kg after the last dose of morphine in day six and withdrawal signs including weight loss and jumping were measured. Ketotifen effects were assessed in two methods of acute and chronic administration to define its role in the expression and induction of morphine tolerance and dependence, respectively. Results: Data showed that ketotifen causes antinociceptive effects in a dose-dependent manner while its 2 mg/kg dose, as a subeffective dose, shows no analgesic effect and did not change the antinociceptive threshold of acute morphine in no-tolerant mice. Co-administration of ketotifen with morphine in the induction phase attenuated morphine tolerance and reduced withdrawal signs. Furthermore, acute administration of ketotifen 2 mg/kg at day six reduced expression of morphine tolerance and dependence. Conclusions: Accordingly, ketotifen can be used in conjunction with opioids to reduce opioid tolerance and dependence. It can also be considered in treating people addicted to opioids.