Development of acute tolerance to the effects of naloxone on the hypothalamic-pituitary-luteinizing hormone axis in the male rat

Although the development of acute and chronic tolerance to opiate agonists, mixed agonists-antagonists and endogenous opioid peptides is well established, tolerance to naloxone, a 'pure' opiate antagonist, has never been reported. In the present studies, the acute development of tolerance to the effects of naloxone on the hypothalamic-pituitary-luteinizing hormone (LH) axis was demonstrated in the male rat. Naloxone causes rapid, dose-dependent increases in serum LH levels in the male, apparently by blocking the actions of an endogenously occurring opioid peptide which normally inhibits the release of LH. We found that naloxone (2 mg/kg) pretreatment markedly reduced naloxone-induced increases in serum LH after a second identical injection if the interval between the first and second injections was 2 to 4 hr. Serum LH levels had returned to control levels long before (approximately 60 min) the second injection. Normal naloxone-induced increases in serum LH were obtained if the interval between the first and second injections was 6 hr or more. This diminished LH-response to a second naloxone injection satisfied the two pharmacological criteria for the establishment of tolerance: a parallel shift to the right in the dose-response curve; and a reduced response to naloxone at the same brain concentration of the antagonist in 'tolerant' vs nontolerant rats. Furthermore, a number of factors, unrelated to tolerance per se, which could have contributed to the effects observed were ruled out. It appears, therefore, that the results presented may provide the first evidence for the development of acute tolerance to a pure opiate antagonist.