Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists.

The discriminative stimulus effects of butorphanol were examined in separate groups of pigeons trained to discriminate either a low (0.1 mg/kg), medium (1.0 mg/kg) or high (5.6 mg/kg) dose of butorphanol from saline. The mu-selective opioid antagonist naloxone was considerably more potent than the delta-selective opioid antagonist naltrindole in antagonizing the effects of butorphanol. In each of the training dose groups, the mu opioid agonists morphine, l-methadone and fentanyl, as well as buprenorphine, (-)-pentazocine, nalbuphine, (-)-metazocine and nalorphine, substituted completely for the butorphanol stimulus. The rank order of potency for these compounds in substituting for the butorphanol stimulus was similar across training dose groups and similar to those reported in studies in which fentanyl or morphine were used as training stimuli. (-)-N-allylnormetazocine (NANM) and levallorphan substituted completely for the butorphanol stimulus in the low-dose group, and substituted partially for and antagonized partially the butorphanol stimulus in the medium- and high-dose groups. The kappa opioid agonists spiradoline, bremazocine, U50,488 and U69,593 substituted partially for butorphanol in the low-dose group, an effect that was not reversed by naloxone. In the medium- and high-dose groups, these kappa opioid agonists produced predominantly saline-appropriate responding. The delta opioid agonist BW373U86 substituted completely for butorphanol in the low-dose group, and naltrindole was more potent than naloxone in antagonizing these effects. In the medium- and high-dose groups, BW373U86 substituted partially for the butorphanol stimulus. Unlike the substitution patterns produced by the mu, kappa and delta opioid agonists, the sigma/phencyclidine compounds (+)-cyclazocine and (+)-NANM and the barbiturate pentobarbital produced predominantly saline-appropriate responding in all training dose groups. The present findings suggest that opioids with agonist activity at mu, kappa and delta opioid receptors share similar stimulus effects with a low training dose of butorphanol, whereas only opioids with agonist activity at the mu opioid receptor share stimulus effects with a medium and high training dose of butorphanol.