beta-funaltrexamine and enadoline

Squirrel monkeys were trained to discriminate i.m. injections of the kappa-opioid receptor agonist enadoline (0.0017 mg/kg) from saline in a two-lever drug-discrimination procedure. Enadoline produced a reliable discriminative stimulus that was reproduced by the kappa-selective agonists PD 117302, U 50,488, GR 89686A, (-)-spiradoline, ICI 204448, and EMD 61753, and by the mixed-action kappa/mu-agonists bremazocine and ethylketocyclazocine. The discriminative stimulus effects of enadoline were not reproduced by the mu-selective agonist morphine, the delta-selective agonist BW373U86, the mixed-action opioids nalbuphine and nalorphine, or by the less active enantiomers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respectively. The selective mu-opioid antagonist beta-funaltrexamine (10.0 mg/kg) did not appreciably alter the dose-effect function for enadoline in any subject. However, the nonselective and kappa-selective opioid antagonists quadazocine (0.03-3.0 mg/kg) and nor-BNI (3-10 mg/kg), and the mixed-action opioid nalbuphine (0.3-30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were long-lasting and did not distinguish between drugs purported to act at different kappa-receptor subtypes. The present results bolster the view that common discriminative stimulus effects of enadoline and other opioids are mediated by kappa-agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine support the idea that it acts with low efficacy at kappa-opioid receptors.

Topics: Animals; Benzofurans; Discrimination Learning; Dose-Response Relationship, Drug; Male; Nalbuphine; Naltrexone; Narcotic Antagonists; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri; Thiophenes

In mammals, opioids act by interactions with three distinct types of receptors: mu, delta, or kappa opioid receptors. Using a novel assay of antinociception in the Northern grass frog, Rana pipiens, previous work demonstrated that selective mu, delta, or kappa opioids produced a potent antinociception when administered by the spinal route. The relative potency of this effect was highly correlated to that found in mammals. Present studies employing selective opioid antagonists, beta-FNA, NTI, or nor-BNI demonstrated that, in general, these antagonists were not selective in the amphibian model. These data have implications for the functional evolution of opioid receptors in vertebrates and suggest that the tested mu, delta, and kappa opioids mediate antinociception via a single type of opioid receptor in amphibians, termed the unireceptor.

Topics: Acetic Acid; Analgesics; Animals; Benzofurans; Female; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Pyrrolidines; Rana pipiens; Receptors, Opioid; Time Factors

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