Opiate withdrawal-induced hyposensitivity to naloxone's effects on serum luteinizing hormone in the male rat

In previous studies, it was demonstrated that morphine pellet implantation markedly sensitized adult male rats to the subsequent elevations in serum luteinizing hormone (LH) levels produced by the opiate antagonist, naloxone. The present studies were carried out to examine the persistence of this phenomenon upon pellet removal and to characterize the relationship between naloxone-induced alterations in serum LH and the development and dissipation of precipitated withdrawal behavior. We found an excellent correlation between both the development and dissipation of naloxone-precipitated withdrawal behavior and hypersensitivity to naloxone's effects on serum LH. However, although there was no evidence of protracted effects of chronic morphine administration upon pellet removal as assessed by withdrawal behavior, the effects of naloxone on serum LH levels did not return to normal for nearly a week postwithdrawal. The markedly enhanced sensitivity to naloxone normally observed in the pellet-implanted animal dissipated immediately after pellet removal (6-24 hr), but, rather than exhibiting normal levels of responding, morphine-withdrawn animals were markedly hyposensitive to naloxone. The antagonist did not increase LH at all in pellet-withdrawn animals and, in fact, appeared to depress them at many doses in the acutely withdrawn animal; normal responses did not return until 4 to 7 days after pellet removal. The mechanisms underlying the striking withdrawal-induced reversal of naloxone's effects on serum LH levels are presently unclear, but our data are consistent with the hypothesis that chronic morphine administration induces a fundamental change in the sensitivity of the endogenous opioid-mediated control of LH, which takes some time to revert to normal upon abrupt termination of opiate administration.