buprenorphine and ketazocine

Withdrawal contractures following brief exposure of guinea-pig ileum to enkephalin analogues, dynorphin A-(1-13) and beta-endorphin and the opiate drugs morphine, ketocyclazocine, buprenorphine and MR2034 were investigated. Following 2 min contact with the ileum a withdrawal contracture was induced by washout of (Met5)- and (Leu5)-enkephalin and by several enkephalin analogues but not by washout of (D-Ala2,D-Leu5)-enkephalinamide or any of the other drugs tested. Addition of naloxone precipitated withdrawal to all opioids tested except the kappa receptor preferential drugs ketocyclazocine and MR2034 and the mu receptor partial agonist, buprenorphine. The heights of the withdrawal contractures to enkephalin analogues were found to be dependent on the concentration of agonist and of naloxone, and on the duration of the contact period of opioid with the ileum. The naloxone-precipitated withdrawal responses to morphine, dynorphin A-(1-13) and the washout withdrawal response to (Met5)-enkephalin were inhibited by substance P antagonists thus supporting the previous proposal that substance P mediates the opiate withdrawal response. This study has shown that mu receptor agonists produced dependence in the guinea-pig ileum revealed by a withdrawal contracture on addition of naloxone, whereas dependence on kappa receptor agonists could not be revealed with naloxone. Since the guinea-pig ileum preparation has millimicron and kappa receptors it was concluded that the endogenous opioid peptides, enkephalins, beta-endorphin and dynorphin A-(1-13), all induced dependence by acting on mu receptors in this preparation.

Topics: Animals; Benzomorphans; Buprenorphine; Cyclazocine; Endorphins; Ethylketocyclazocine; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Naloxone; Narcotics; Substance P; Substance Withdrawal Syndrome

The effects of naloxone were examined over a period of three and a half years in squirrel monkeys responding under a mult FR, FI schedule of food presentation. During the initial observation of naloxone's effects, monkeys were drug naive. At that time, doses of naloxone up to 3.0 mg/kg had very little effect on rates of responding under the multiple schedule. The effects of naloxone were then examined in combination with meperidine. Doses of naloxone between 0.3 and 3.0 mg/kg produced a dose-dependent antagonism of meperidine's effects. Monkeys were then exposed to ketocyclazocine and phencyclidine, alone and in combination with naloxone. When the naloxone dose-effect curve was redetermined subsequently, it had shifted to the left. Monkeys were then exposed to buprenorphine and diprenorphine, alone and in combination with naloxone. Redetermination of the naloxone dose-effect curve following this exposure revealed a further shift to the left. The effects of naloxone were then reexamined in combination with meperidine, and it was found that the leftward shift in the naloxone dose-effect curve was not accompanied by a decrease in the doses of naloxone which would reverse the effects of meperidine. Naloxone's effects were then examined in combination with either acute or chronic diazepam. The naloxone dose-effect curve determined during the chronic diazepam regimen was shifted to the right of that obtained prior to chronic diazepam.

Topics: Animals; Buprenorphine; Cyclazocine; Diprenorphine; Dose-Response Relationship, Drug; Drug Interactions; Ethylketocyclazocine; Male; Meperidine; Naloxone; Phencyclidine; Reaction Time; Saimiri

The effects of a number of relatively pure opiate antagonists (naloxone, naltrexone, diprenorphine), and putative mu- (morphine, etorphine) and kappa- (ketocyclazocine, ethylketocyclazocine) receptor agonists on sweetened condensed milk intake were examined over a broad range of doses in non-deprived rats and squirrel monkeys. The antagonists consistently decreased milk intake in both the rat and squirrel monkey. There were, however, species differences: diprenorphine was 30 times more potent than either naloxone or naltrexone in the squirrel monkey, but was of similar potency in the rat. The effects of the opiate agonists were more variable than those of the antagonists. In both species, all agonists decreased milk intake at high doses that also produced behavioral depression. Significant increases in drinking were produced only by low doses of ketocyclazocine and ethylketocyclazocine in the rat. The suppression of milk intake by the antagonists supports a modulatory role of opiate receptors in the control of drinking behavior, however, the effects of the agonists on drinking are less easily interpreted within this conceptual framework.

Topics: Animals; Buprenorphine; Cyclazocine; Diazepam; Diprenorphine; Drinking; Ethylketocyclazocine; Etorphine; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri; Taste