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Pharmacological specificity of enhanced sensitivity to naltrexone in rats

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Abstract

Rats treated weekly with cumulative doses (1–100 mg/kg, IP) of naltrexone develop an enhanced sensitivity to the operant response-rate decreasing effect of naltrexone. In the present experiment the pharmacological specificity of that enhanced sensitivity was determined by testing a variety of drugs for cross-sensitivity to naltrexone. Cross-sensitivity was evaluated with two procedures. In one, dose-effect functions were determined for each of the test compounds before and after the development of enhanced sensitivity to naltrexone in a single group of rats. In the second procedure, one group of rats was made sensitive to naltrexone, while a second was not. Test compounds were then evaluated in both groups. For both procedures, a shift to the left in the dose-effect functions similar to naltrexone was considered evidence of cross-sensitivity. Of the opioid antagonists tested, only naloxone showed clear cross-sensitivity to naltrexone, although MR 2266 and diprenorphine also showed evidence of cross-sensitivity. The opioid antagonist quadazocine did not show cross-sensitivity to naltrexone on the day of testing, although some evidence of cross-sensitivity was evident 24 h later. In addition, the dose-effect function ford-amphetamine was significantly changed following naltrexone treatment. No evidence of cross-sensitivity was observed for the optical isomer of naloxone,d-naloxone, or for naloxone's quaternary derivative, naloxone methiodide. None of the opioid agonists or agonist-antagonists tested showed cross-sensitivity to naltrexone (i.e. morphine, U-50, 488H, ethylketocyclazocine,N-allylnormetazocine and pentazocine). The non-opioid drugs chlordiazepoxide and phencyclidine also failed to show evidence of cross-sensitivity. However, the dose-effect curves for chlordiazepoxide were shifted significantly to the right following naltrexone treatment. The results of the present experiment indicate that the enhanced sensitivity which develops to naltrexone in rats is stereospecific and centrally mediated. The effect is specific, in that it does not appear to confer changes in the behavioral effects of non-opioids or even opioid agonists.

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Authors and Affiliations

  1. Preclinical Pharmacology Laboratory, National Institute on Drug Abuse, Addiction Research Center, P.O. Box 5180, 21224, Baltimore, MD, USA

    C. W. Schindler, S. R. Goldberg & J. L. Katz

  2. Department of Pharmacology and Experimental Therapeutics, University of Maryland at Baltimore, 21201, Baltimore, MD, USA

    C. W. Schindler, S. R. Goldberg & J. L. Katz

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  1. C. W. Schindler
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  2. S. R. Goldberg
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  3. J. L. Katz
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Schindler, C.W., Goldberg, S.R. & Katz, J.L. Pharmacological specificity of enhanced sensitivity to naltrexone in rats. Psychopharmacology 110, 60–68 (1993). https://doi.org/10.1007/BF02246951

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  • DOI: https://doi.org/10.1007/BF02246951

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