Stereoselectivity of the stimulus effects of morphine and cyclazocine in the squirrel monkey
Teal, J.J.; Holtzman, S.G.
Journal of Pharmacology and Experimental Therapeutics 215(2): 369-376
1980
ISSN/ISBN: 0022-3565 PMID: 7441501 Document Number: 156552
The stereoselectivity of the discriminative stimulus effects of morphine and cyclazocine was evaluated in separate groups of squirrel monkeys trained to discriminate between saline and either 3.0 mg/kg l-morphine or 0.1 mg/kg dl-cyclazocine in a 2-choice avoidance paradigm. Stimulus control of behavior was defined as the reliable completion of at least 22 trials of a 25 trial session on the choice lever appropriate for the training drug or saline. Stimulus generalization tests were conducted in both groups of monkeys with the following pairs of enantiomers: d- and l-cyclazocine, levorphanol and dextrorphan, d- and l-methadone and levomethorphan and dextromethorphan. Levo- and dextrocyclazocine (0.03 and 3.0 mg/kg, respectively) substituted for the training dose of dl-cyclazocine (i.e., produced comparable stimulus control) but produced only intermediate levels of morphine-appropriate responding. Levorphanol, l-methadone and levomethorphan substituted for morphine and engendered intermediate levels of cyclazocine-appropriate responding with a potency order in both groups of levorphanol > l-methadone > levomethorphan. The dextro-isomers of these 3 drugs produced various levels of morphine- and cyclazocine-appropriate responding and dextromethorphan substituted for cyclazocine but the dextro-isomers did not display a prominent order of relative potency in either group of monkeys. Compounds with morphine-like stimulus effects were antagonized by 0.03-0.3 mg/kg naltrexone. A higher dose of naltrexone (i.e., 1.0 mg/kg) blocked the cyclazocine-appropriate responding produced by l- and dl-cyclazocine in the cyclazocine-trained monkeys but not that produced by the dextro-isomers. The stimulus effects of both morphine and cyclazocine are stereoselective for the levo-isomer and are mediated through different populations of opiate receptors. The dextro-isomers of the opiates produce prominent discriminative stimulus effects which appear to more closely resemble those of dl-cyclazocine than those of l-morphine and which are probably not mediated by classical opiate receptors.