An Analysis of Precipitated Withdrawal in Rats Acutely Dependent on Morphine

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Abstract
Acute dependence on a single dose of morphine was assessed in Wistar rats by observing the occurrence frequencies of several signs of withdrawal precipitated b naloxone, diprenorphine, Mr2097, Mr1452 [.alpha.-5,9-dimethyl-2-(3-furymethyl)-2''-hydroxy-6,7-benzomorphan] and Mr2266 [(-)5,9-.alpha.-diethyl-2-(3-furymethyl)-2''-hydroxy-6,7-benzomorphan-5 hydrochloride]. 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 precipated withdrawal only in l-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 .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-50488 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.