Discriminative stimulus effects of enadoline in pigeons

The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/ kg) producing greater than or equal to 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced greater than or equal to 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA(2) = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in greater than or equal to 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion greater than or equal to 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.