Pharmacological specificity of enhanced sensitivity to naltrexone in rats

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 for d-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.(ABSTRACT TRUNCATED AT 250 WORDS)