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.