beta-funaltrexamine and quadazocine

An unbiased conditioned place preference paradigm was used to evaluate the reward effect of selective endogenous mu-opioid ligands, endomorphin-1 and endomorphin-2, in male CD-1 mice. Pre- and post-conditioning free-movement were measured on day 1 and day 5, respectively. Conditioning sessions were conducted twice daily from day 2 through day 4 consisting of the alternate injection of conditioning drug or vehicle. Intracerebroventricular (i.c.v.) injection of endomorphin-1 (0.3-10 microg) induced place preference in a dose-dependent manner; whereas, endomorphin-2 (1-10 microg) dose-dependently induced place aversion. Both endomorphin-1-induced place preference and endomorphin-2-induced place aversion were blocked by pretreatment i.c.v. with mu-opioid receptor antagonist, beta-funaltrexamine. Selective delta-opioid receptor antagonist, naltrindole, co-administered i.c.v. with endomorphin-1 or endomorphin-2 did not affect reward effect. However, endomorphin-2-induced place aversion, but not endomorphin-1-induced place preference, was blocked by the i.c.v.-administered selective kappa-opioid receptor antagonist, WIN 44,441-3. It is concluded that endomorphin-1 produces conditioned place preference, which is mediated by the stimulation of mu-, but not delta- or kappa-opioid receptors, while endomorphin-2 produces conditioned place aversion, which is mediated by the stimulation of mu- and kappa-, but not delta-opioid receptors.

Topics: Animals; Azocines; Conditioning, Operant; Injections, Intraventricular; Ligands; Male; Mice; Naltrexone; Oligopeptides; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

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

Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (CI-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel monkeys that responded under a schedule of shock titration. When given alone, each of these agonists increased the intensity at which the monkeys maintained shock 50% of the time (median shock level, MSL). Lower doses of spiradoline, enadoline and U69,593 increased response rates in some monkeys and higher doses decreased response rates in all monkeys. When given in combination with the opioid antagonist quadazocine, the dose-effect curves of each agonist, both for MSL and response rates, were shifted to the right in a dose-related and parallel manner. The slopes for the regression lines of the Schild plots for each agonist-quadazocine interaction approximated unity and apparent pA2 values for quadazocine in combination with these agonists ranged between 6.68 and 6.81 for MSL and between 6.63 and 6.87 for response rate. The effects of these agonists were not changed by an 8.0 mg/kg dose of beta-funaltrexamine that markedly antagonized the effects of morphine. These results parallel those previously obtained with other kappa agonists, such as bremazocine and U50,488 and suggest that the antinociceptive effects of spiradoline, enadoline and U69,593 in the shock-titration procedure in squirrel monkeys relate to activity at non-mu, probably kappa, opioid receptors.

Topics: Analgesics; Animals; Azocines; Benzeneacetamides; Benzofurans; Dose-Response Relationship, Drug; Male; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid, kappa; Saimiri

In rhesus monkeys, kappa opioid agonists have been shown to increase urinary output, increase tail-withdrawal latencies from warm water and produce distinct discriminative stimulus effects. In order to explore further the relation between these effects and activity at the kappa opioid receptor type, the antagonist activity of quadazocine against several kappa opioid agonists was examined with the tail-withdrawal and drug-discrimination procedures. Quadazocine dose dependently antagonized the increases in tail-withdrawal latency produced by the kappa agonists bremazocine, ethylketazocine and U-50, 488, as well as the discriminative stimulus effects of these drugs. The dose-ratio analysis of Schild revealed apparent pA2 values for quadazocine in combination with bremazocine, ethylketazocine and U-50, 488 of 6.1, 6.4 and 6.4, respectively, with the tail-withdrawal procedure and 6.3, 6.4 and 6.1, respectively, with the drug-discrimination procedure. Quadazocine also antagonized the effects of a mu agonist (morphine) in the tail-withdrawal procedure, and the apparent pA2 value for these data was 8.2. The activity of the mu-selective alkylating agent, beta-funaltrexamine (beta-FNA), was examined alone and in combination with the kappa agonist ethylketazocine in the urinary-output, tail-withdrawal and drug-discrimination procedures. At about 30 to 60 min postinjection, beta-FNA alone produced ethylketazocine-appropriate responding under the drug-discrimination procedure and increased urine output but did not increase tail-withdrawal latencies. At 24 to 48 hr postinjection, beta-FNA did not antagonize effects of ethylketazocine in any of the three procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Azocines; Benzomorphans; Cyclazocine; Diuresis; Endorphins; Ethylketocyclazocine; Female; Hot Temperature; Macaca mulatta; Male; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Reaction Time; Tail

The behavioral effects of the opioid receptor alkylating agent beta-funaltrexamine (beta-FNA) were assessed in normal (drug-naive) and morphine-dependent rhesus monkeys. In normal monkeys, beta-FNA (10 mg/kg s.c.) produced muscle relaxation and stupor, which could be reversed by the opioid antagonist Win 44,441. Given as a 48-hr pretreatment, beta-FNA antagonized the behavioral effects of acute morphine, but not those of two kappa agonists, ethylketazocine and Mr 2033 (UM 1072). In morphine-dependent monkeys, beta-FNA (10 mg/kg, s.c. and 0.003 mg i.c.v.) precipitated severe abstinence which lasted for 3 days. beta-FNA was more than 13,000 times more potent in precipitating withdrawal after i.c.v. than s.c. administration, whereas naltrexone and Win 44,441 were equipotent by these routes. Deprivation-induced abstinence (14 hr) and withdrawal of similar severity precipitated by naltrexone, Win 44,441 or naloxonazine were suppressed completely by 17.5 mg/kg of morphine. In contrast, 320 mg/kg of morphine failed to suppress completely a withdrawal syndrome of the same severity elicited by s.c. or i.c.v. beta-FNA. These data are consistent with the view that beta-FNA has reversible opioid agonist and insurmountable mu selective antagonist activity in the rhesus monkey.

Topics: Animals; Azocines; Behavior, Animal; Dose-Response Relationship, Drug; Injections, Intraventricular; Injections, Subcutaneous; Macaca mulatta; Morphine; Muscle Relaxation; Naloxone; Naltrexone; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Pigeons trained to peck a key on a fixed-ratio 20 schedule of food presentation were used to evaluate the antagonistic and rate-suppressing effects of several opioid antagonists. Antagonism was measured as an increase in the dose of morphine necessary to suppress responding. Antagonist pretreatments increased the suppressing dose of morphine, although the magnitude of the increase varied markedly among different antagonists. Rank order of the maximum increase in the suppressing dose of morphine that each antagonist produced was: naltrexone = WIN 44,441 greater than beta-funaltrexamine greater than naloxone = buprenorphine greater than MR 2266 greater than diprenorphine. The time course of morphine antagonism also differed among antagonists. For example, buprenorphine was not an effective antagonist when administered 10 min before morphine, but was effective when administered either 2 or 12 hr before morphine. beta-Funaltrexamine and WIN 44,441 had the longest durations of antagonist action; each antagonized the rate-suppressing effects of morphine from 10 min to 24 hr. The effective antagonistic dose range (i.e., doses which blocked the rate-suppressing effects of morphine without affecting response rate when administered alone) and maximum increase in the suppressing dose of morphine were highly correlated, suggesting that the direct effects of most of these antagonists on responding may limit their effectiveness as morphine antagonists.

Topics: Animals; Azocines; Benzomorphans; Buprenorphine; Columbidae; Conditioning, Operant; Diprenorphine; Dose-Response Relationship, Drug; Morphine; Naloxone; Naltrexone; Narcotic Antagonists