An analysis of precipitated withdrawal in rats acutely dependent on morphine

Acute dependence on a single dose of morphine was assessed in Wistar rats by observing the frequencies of occurrence of several signs of withdrawal precipitated by naloxone, diprenorphine, Mr2097, Mr1452 and Mr2266. Naloxone significantly precipitated urination, paw shakes, head shakes and chewing. Diprenorphine significantly precipitated urination and chewing. Mr2097 precipitated urination, head shakes, teeth chattering and chewing. The selective kappa antagonists Mr1452 and Mr2266 significantly precipitated only urination and teeth chattering. Signs of the precipitated withdrawal by Mr2097 were mediated by stereoselective opioid receptors, as the other diastereoisomer, Mr2097, did not precipitate them. Stereospecific opioid receptors were also involved in the induction of acute dependence, as naloxone precipitated withdrawal only in I-methadone-treated rats, but not in d-methadone treated rats. All the opioid antagonists produced at least some degree of "abstinoid" signs in morphine-free rats which might be caused by the blockade of endogenous opioids acting on mu and/or kappa receptors. The signs of withdrawal precipitated by naloxone and Mr2097 might be primarily mediated by mu receptors, those of diprenorphine by both mu and kappa receptors, and those by Mr1452 and Mr2266 were likely to be selectively mediated by kappa receptors. The latter aspect was further supported by experiments showing that the novel kappa agonist U-50488H did not precipitate withdrawal. A low degree of precipitation of withdrawal by Mr1452 and Mr2266 and the absence of precipitation of abstinence by U-50488H might be related to either a lack or an existence of a low proportion of kappa receptors in rat brain. Further experiments using selective agonists and antagonists are needed to evaluate these findings.