heroin and naltrindole

Recent studies have reported differences in the receptor mechanisms and intrinsic efficacies of heroin and its metabolites 6-acetylmorphine and morphine in rodents. The present study examined the generality of these findings to rhesus monkeys using two behavioral procedures. In an assay of schedule-controlled behavior, response rates were recorded under a fixed-ratio 30 schedule of food presentation. In an assay of thermal nociception, tail-withdrawal latencies were measured from warm water (42-58 degrees C). Heroin, 6-acetylmorphine and morphine produced dose-dependent rate-decreasing and antinociceptive effects. Antagonism studies were conducted with the competitive mu-selective antagonist quadazocine, the competitive delta-selective antagonist naltrindole, and the irreversible mu-selective antagonist beta-funaltrexamine (beta-FNA). Quadazocine dose-dependently antagonized the effects of all three opioids. Quadazocine pA2 values were similar across drugs and assays (7.4-7.8) and similar to quadazocine pA2 values for antagonism of other mu agonists. In contrast, naltrindole did not alter the effects of any of the opioids. beta-FNA antagonized the rate-decreasing and antinociceptive effects of heroin and morphine. Dose-effect data for heroin- and morphine-induced antinociception alone and after beta-FNA treatment were used to estimate in vivo apparent efficacy values (tau). Tau values (95% confidence limits) were 8.1 (6.9-9.6) for heroin and 2.6 (2.5-2.9) for morphine, but this difference is relatively small. These results suggest that the rate-decreasing and antinociceptive effects of heroin, 6-acetylmorphine and morphine are mediated by pharmacologically similar populations of mu opioid receptors in rhesus monkeys. The in vivo apparent efficacy of heroin at mu receptors was similar to or only slightly greater than that of morphine.

Topics: Animals; Azocines; Behavior, Animal; Dose-Response Relationship, Drug; Food; Heroin; Hot Temperature; Macaca mulatta; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Pain Measurement

In this study a rat self-administration model was used to examine the effects of training dose and time in the session on the dose-effect curve for heroin. Doses of heroin lower than 5.4 microg/inf maintained higher rates of drug intake in animals trained with 5.4 microg/inf compared to 18 microg/inf. Doses greater than 5.4 microg/inf maintained similar rates of intake in both groups of animals. The dose-response curve was shifted downward and to the right as the session progressed for animals trained with 5.4 microg/inf of heroin; however, the shift in the dose-intake curve over the session was less pronounced when the training dose was 18 microg/inf. Naltrexone and naltrindole were administered to animals in which responding was engendered with infusions of 5.4 microg of heroin to determine the effects of these antagonists in the context of time is the session. The potency of naltrexone decreased across the 4 h of the session with a time course that was consistent with literature reports on the elimination kinetics of naltrexone in rat brain. In contrast, there was not a significant interaction between naltrindole dose and session time. Therefore, the rates of heroin intake in rats are dependent not only upon the dose available for self-administration, but upon the session time and training dose as well.

Topics: Animals; Dose-Response Relationship, Drug; Heroin; Male; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Rats; Rats, Inbred F344; Self Administration; Time Factors

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

Antagonists selective for mu, delta and kappa-opioid receptors were evaluated for their effects on responding maintained by i.v. injections of heroin (60.0 micrograms/kg/injection) in rats during daily 3-hr sessions. Under base-line conditions, rats self-administered 10 to 20 heroin injections during each session, and injections were separated by relatively constant interinjection intervals of about 10 to 20 min. The mu-selective antagonist beta-funaltrexamine (beta-FNA; 5.0-20.0 mg/kg, s.c.) produced a dose-dependent increase in responding for heroin, with some doses of beta-FNA producing an extinction-like pattern of responding. These results were qualitatively similar to the effect obtained by lowering the unit dose per injection of heroin. The mu 1-selective antagonist naloxonazine (NXZ; 7.5-30.0 mg/kg, i.v.) and the delta-selective antagonist naltrindole (1.0-17.0 mg/kg) also produced dose-dependent increases in heroin self-administration, but neither naloxonazine nor naltrindole produced extinction-like patterns of responding. The kappa-selective antagonist nor-binaltorphimine (nor-BNI; 5.0-10.0 mg/kg, s.c.) had no effect on heroin self-administration. These results indicate that mu receptors play an important role in mediating the reinforcing effects of heroin in the rat. Delta and mu 1 receptors, but not kappa receptors, may also be involved.

Topics: Animals; Heroin; Male; Naloxone; Naltrexone; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration