Differential antagonism by naltrexone of the effects of opioids on a fixed-ratio discrimination in rats

JM Moerschbaecher, C Devia and C Brocklehurst

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans.

In the presence of a stimulus above the center lever, rats were required to complete one of two fixed-ratios (FRs) on the center lever (FR 8 or FR 16). Completion of the ratio turned off the center-lever stimulus and produced a stimulus above each of the two side levers. If the completed ratio was high (e.g., FR 16), a response on the left lever produced a food pellet. If the ratio was low (e.g., FR 8) a response on the right lever produced food. Errors produced a brief timeout. When administered alone, morphine, cyclazocine, pentazocine, dl-N-allylnormetazocine (NANM), d-NANM, I-NANM and phencyclidine each produced dose-related decreases in accuracy and response rate. Ketocyclazocine decreased response rate in a dose-related manner but had little or no effect on accuracy. Naltrexone (0.1 mg/kg) shifted to the right by approximately 0.75 log unit the morphine dose-effect curves. This same dose of naltrexone tended to produce greater antagonism of the effects of pentazocine on accuracy than on rate which was shifted by only 0.25 log unit. Naltrexone (0.1 mg/kg) produced little or no antagonism of the effects of cyclazocine, whereas naltrexone (1 mg/kg) shifted the dose-effect curves to the right by about 0.25 log unit. Naltrexone (0.1 and 1 mg/kg) shifted the ketocyclazocine dose-effect curves to the right by approximately 0.5 and 1 log unit, respectively. Although variable among subjects, across a range of doses (0.1-10 mg/kg), naltrexone failed to antagonize the effects of dl-NANM, d-NANM, l-NANM and phencyclidine. Rather, in some subjects naltrexone tended to shift the dose-effect curves to the left. Fluphenazine (0.1 mg/kg) also failed to antagonize the effects of d-, l- NANM and phencyclidine. In summary, whereas mu and sigma agonists produce qualitatively similar effects on the performance of a discrimination in the rat, they do so through different mechanisms of action.

Volume 244, Issue 1, pp. 237-246, 01/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics