diprenorphine and Morphine-Dependence

The purpose of the present study is to compare the capacity of opioid antagonists to elicit withdrawal jumping in mice following two acute pretreatment doses of the opioid agonist morphine. Antagonists that precipitate vigorous withdrawal jumping across both morphine treatment doses are hypothesized to be strong inverse agonists at the mu-opioid receptor, whereas antagonists that elicit withdrawal jumping in mice treated with the high but not the low dose of morphine are hypothesized to be weak inverse agonists. Male, Swiss-Webster mice (15-30 g) were acutely treated with 56 or 180 mg kg(-1) morphine 4 h prior to injection with naloxone, naltrexone, diprenorphine, nalorphine, or naloxonazine. Vertical jumping, paw tremors, and weight loss were recorded. Naloxone, naltrexone, and diprenorphine produced withdrawal jumping after 56 and 180 mg kg(-1)morphine pretreatment. Nalorphine and naloxonazine produced moderate withdrawal jumping after 180 mg kg(-1) morphine pretreatment, but failed to elicit significant withdrawal jumping after 56 mg kg(-1) morphine pretreatment. Nalorphine and naloxonazine blocked the withdrawal jumping produced by naloxone. All antagonists produced paw tremors and weight loss although these effects were generally not dose-dependent. Taken together, these findings reveal a rank order of negative intrinsic efficacy for these opioid antagonists as follows: naloxone=naltrexone> or =diprenorphine>nalorphine=naloxonazine. Furthermore, the observation that nalorphine and naloxonazine blocked the naloxone-induced withdrawal jumping provides additional evidence that nalorphine and naloxonazine are weaker inverse agonists than naloxone.

Topics: Animals; Behavior, Animal; Body Weight; Brain; Diprenorphine; Dose-Response Relationship, Drug; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Substance Withdrawal Syndrome; Tremor

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.

Topics: Animals; Diprenorphine; Humans; Male; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism; Substance Withdrawal Syndrome

Abstinence signs were precipitated in rats by naloxone (1 mg - kg-1 s.c.) injected at various times (from 1.5 to 16 h) after a single dose of morphine hydrochloride (15 or 50 mg - kg-1 s.c.) administered in aqueous solution. Increasing the dose of morphine increased the latency of the phenomena and the duration of the underlying state; "shifts" of signs as described by Bläsig et al. (1974) in chronically morphinized rats also occurred when increasing the dose of morphine and the time interval between the injections of morphine and of naloxone. Naltrexone and diprenorphine were also effective. These three antagonists, given before morphine, were able to prevent precipitated abstinence: however, naloxone was almost ineffective when the higher dose of morphine was used and when the time interval was long. In these latter conditions, naltrexone was definitely more effective and longer acting and diprenorphine still more so. The same characteristics were found for the protective action of the three antagonists in acutely morphinized mice and the same order for their potencies in precipitating abstinence in acutely morphinized mice. Like naloxone, naltrexone and diprenorphine facilitated a nociceptive reaction in normal mice. The abstinence signs precipitated in acutely morphinized rats or mice are probably not unmasked excitatory effects of morphine as such effects should have been increased rather than inhibited by previous administration of specific antagonists; they might correspond to potentiated effects of the antagonists themselves. The prevention by specific antagonists of the abstinence syndrome is most simply interpreted by antagonism (direct or indirect) of dependence induction, but other interpretations are not excluded.

Topics: Animals; Diprenorphine; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Naloxone; Naltrexone; Rats; Substance Withdrawal Syndrome; Time Factors