Further characterization of the discriminative stimulus effects of spiradoline.
The results of a previous study in rats indicated that spiradoline has pharmacologically selective discriminative effects that are mediated by kappa-opioid receptors. However, the training dose, 3.0 mg/kg, increased response latencies, suggesting that it was relatively high. The current study was performed to characterize further the discriminative effects of spiradoline by using a lower training dose, 1.0 mg/kg, and testing a larger number of drugs for generalization with spiradoline. Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and spiradoline were not different from each other. The rats generalized dose dependently and completely to other kappa-opioid agonists that have relatively high efficacy: ethylketocyclazocine, U69,593, and U50,488. They generalized partially to ketocyclazocine, (-)-N-allylnormetazocine, and DuP 747, and not at all to cyclazocine, butorphanol, nalorphine, and pentazocine, discriminable opioids that have relatively low efficacy at kappa-opioid receptors, or to morphine and dextromethorphan, discriminable drugs that do not act at kappa-opioid receptors. The discriminative effects of spiradoline were unaffected by the mu-opioid antagonist beta-funaltrexamine, but were blocked completely for at least 4 weeks by the kappa-opioid antagonist nor-binaltorphimine. Thus, spiradoline-like stimulus control of behavior remains kappa-opioid selective, and continues to have a high efficacy requirement even at a training dose that does not impair performance.
Holtzman
S G
SG
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D004193:Discrimination Learning / Q000187:drug effects*; D004347:Drug Interactions; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D018733:Nicotinic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013764:Tetrahydronaphthalenes; C076987:DuP 747; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; C051272:spiradoline