Agonist and antagonist activity of kappa opioids in the squirrel monkey: I. Antinociception and urine output.
The present study was conducted to evaluate the agonist and antagonist properties of kappa opioids in the squirrel monkey shock titration procedure. The opioid antagonist naltrexone, the kappa agonists U50,488, bremazocine, ethylketazocine and tifluadom, and the mu agonist l-methadone were administered alone and in combination with a single dose of the mu agonist morphine. When administered alone, all opioids except naltrexone produced dose-dependent increases in median shock level (the intensity below which monkeys maintained shock 50% of the time). In addition, all kappa agonists produced increases in urine output, whereas naltrexone and l-methadone did not. When combined with morphine, naltrexone and all kappa agonists antagonized, at least partially, morphine-induced increases in median shock level, whereas l-methadone did not. Naltrexone and the four kappa agonists also shifted an l-methadone dose-effect curve rightward in a parallel manner; however, the shifts produced by naltrexone were greater in magnitude than those produced by the kappa agonists. These studies demonstrate that a variety of kappa agonists can act as mu antagonists in a primate model of analgesia, although antagonist activity of kappa opioids appears to be limited by their agonist activity in this procedure. Order of potency among the kappa agonists for analgesic, diuretic and antagonist effects was very similar (bremazocine greater than ethylketazocine greater than tifluadom greater than or equal to U50,488), as was the dose range for peak diuretic and antagonist effects, suggesting that mu antagonism among kappa agonists may be kappa-mediated in the squirrel monkey.
Craft
R M
RM
Department of Psychology, University of North Carolina, Chapel Hill.
Dykstra
L A
LA
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001575:Benzomorphans / Q000494:pharmacology; D004347:Drug Interactions; D016314:Ethylketocyclazocine / Q000494:pharmacology; D008297:Male; D008691:Methadone / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists; D009294:Narcotics / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012453:Saimiri; D014554:Urination / Q000187:drug effects*
D000700:Analgesics; D001575:Benzomorphans; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D001569:Benzodiazepines; D016314:Ethylketocyclazocine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C027248:bremazocine; C035470:tifluadom; D008691:Methadone