diprenorphine and Body-Weight

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

Although chronic administration of naloxone has been reported to reduce food intake and body weight in rats, there have been no comparable investigations using a nonhuman primate. We examined the effects of repeated injections of two long acting opiate antagonists - naltrexone and diprenorphine - on the ad libitum intake of a nutritional complete liquid diet and on body weight in squirrel monkeys. Naltrexone binds with highest affinity to the mu opioid receptor whereas diprenorphine binds with equally high affinity to several subtypes of opioid receptor. Diprenorphine (ED50 = 0.01 mg/kg) was 22 times more potent than naltrexone (ED50 = 0.22 mg/kg) in decreasing 2 h food intake, suggesting that more than one opioid receptor subtype may be involved in the anorectic effects of opiate antagonists. A 1.0 mg/kg dose of drug reduced 24 h food intake by 50% and was associated with a weekly reduction in body weight of 4 and 5% for naltrexone and diprenorphine, respectively. Thus, in contrast with shorter time intervals, 24 h food intakes were similar for the two drugs, and this was associated with comparable body weight profiles. The decreases in food intake and body weight remained constant over the period of drug administration. Some monkeys showed profuse salivation and "wet dog shakes" after 4 days of treatment with the 1.0 mg/kg dose but not after 1 day. Therefore, opiate antagonists given chronically to monkeys reduced food intake and body weight in a dose-dependent manner with no evidence of tolerance to these effects.

Topics: Animals; Body Weight; Diprenorphine; Dose-Response Relationship, Drug; Drinking; Eating; Female; Humans; Male; Morphinans; Naloxone; Naltrexone; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri; Salivation