Effect of Tizanidine, Rilmenidine, and Yohimbine on Naloxon-Induced Morphine Withdrawal Syndrome in Mice

In this study using clonidine (a mixed ?2 /I1 receptors agonist), tizanidine (pure ?2-receptor agonist), rilmenidine (I1 receptor agonist) and yohimbine (?2-receptor antagonist), we tried to clarify the role of imidazoline and ?2-receptors in morphine withdrawal syndrome. Morphine-dependence was induced by administration of increasing doses of morphine in mice. After the last administration of morphine, clonidine (0.3 mg/kg, i.p.), tizanidine (1 and 2 mg/kg, i.p.) and rilmenidine (1.5 and 3 mg/kg, i.p.), with / without pretreatment with yohimbine (1 mg/kg, i.p.) were administered 30 min before naloxone (5 mg/kg, i.p.) challenge. Withdrawal symptoms including: jumping, ptosis, piloerection, tremor and diarrhea were recorded. Rilmenidine (3 mg/kg) decreased naloxone-induced jumping and this effect was partially inhibited by yohimbine. Rilmenidine (1.5 mg/kg), tizanidine and clonidine had no significant effect on jumping. None of drugs influenced ptosis. All drugs increased piloerection and decreased diarrhea. Clonidine and tizanidine decreased tremor. We conclude that Imidazoline receptors as well as ?2 receptors are involved in morphine withdrawal symptoms and yohimbine as an ?2-antagonist can suppress at least some effects of imidazoline agonists. It is suggested that ?2-receptors are located down-stream to imidazoline receptors and their blockade can inhibit imidazoline effects.