Date of Award

1980

Degree Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Harbans Lal

Abstract

Separate groups of rats were trained to discriminate the narcotic agonist-antagonist, cyclazocine (1.25 mg/kg), from saline or the pure narcotic agonist, morphine (10 mg/kg), from saline. In the cyclazocine discriminating animals, the interoceptive stimuli produced by cyclazocine were found to be dose related and largely based on central opiate systems in that these effects were reversed by the narcotic antagonist, naloxone. The discriminative stimulus produced by cyclazocine was found to be completely generalized to nalorphine, ethylketocyclazocine, pentazocine and morphine while a lesser degree of generalization was seen to the experimental compounds, U-49, 274A and U-50,788E. The cyclazocine discriminative stimulus did not generalize to apomorphine, d-amphetamine, haloperidol, d-butaclamol, 1-butaclamol, clonidine, desipramine, amitriptyline, aceperone and butorphanol. Cyclazocine generalization to morphine was completely antagonized by naloxone at a dose one-twentieth that required to antagonize the cyclazocine discriminative stimulus itself. At no dose tested did naloxone completely antagonize cyclazocine generalization to nalorphine. A possible dopaminergic component of the cyclazocine discriminative stimulus was demonstrated by attenuation of stimulus strength with the neuroleptics haloperidol, benperidol and d-butaclamol. The discriminative stimulus produced by morphine was also found to be a dose related effect based upon central opiate mechanisms as demonstrated by naloxone reversibility. The discriminative stimulus produced by morphine only partially generalized to cyclazocine and ethylketocyclazocine. Naloxone antagonized the generalization of morphine to cyclazocine but at a dose four times that required to antagonize the morphine discriminative stimulus itself. A possible dopaminergic component of the morphine discriminative stimulus was demonstrated by haloperidol attenuation of stimulus strength. Cyclazocine analgesia, demonstrated using the mouse tail flick procedure, was found to be maximal approximately five minutes following cyclazocine administration. Some analgesic potency was also ~easurable 35 minutes post cyclazocine. The analgesic effects of cyclazocine were found to be reversed by naloxone. Pretreatment with the neuroleptics oxiperomide, clozapine and dexclamol before cyclazocine was found to enhance the analgesic potency of cyclazocine.

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