The influence of chronic treatment with clonidine, yohimbine and idazoxan on morphine withdrawal

Numerous previous attempts have been made to study the involvement of alpha(2)-adrenoceptors in the expression of morphine withdrawal by studying the effects of selective alpha(2)-agonists and antagonists administered immediately before precipitation of withdrawal by an opioid antagonist such as naloxone, In the present investigation, we examined the effects of chronic treatment with clonidine (alpha(2)-agonist), idazoxan and yohimbine (alpha(2)-antagonists), concomitantly administered with morphine, on the expression of the withdrawal signs. In contrast to their acute effects, clonidine potentiated, while yohimbine and idazoxan attenuated the withdrawal signs precipitated by naloxone in morphine-dependent mice. In addition, mice chronically treated only with yohimbine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were not influenced by naloxone administration. Mice chronically treated with clonidine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were further potentiated by naloxone administration. The results suggest that down-regulation of az-adrenoceptors by morphine is a major adaptation contributing to development of dependence on opioids and also point the way to more effective treatment of narcotic dependence. This suggestion was based on the hypothesis that the suppression of noradrenergic system during chronic morphine treatment by alpha(2)-antagonists might diminish noradrenergic hyperactivity and consequently the development of dependence and withdrawal signs.