Exogenous and endogenous opioid-induced enhancements of naloxone's effects on serum luteinizing hormone levels in the male rat

We have previously shown that brief periods of exposure to opiate alkaloid drugs markedly enhance the subsequent effects of the opiate antagonist, naloxone, on serum luteinizing hormone (LH) levels in the male rat. In the present studies, we have found that this phenomenon is not simply a property of opiate drugs, but can be produced by a metabolically stable analog of an endogenously occuring opioid peptide, methionine enkephalin (FK 33-824). These findings suggest that alterations in the sensitivity of those opioid receptors involved in LH-releasing hormone (LHRH) generated in our experimental paradigm may occur under in vivo conditions, particularly since it now appears that endogenous opioids are released in an episodic manner like most neurotransmitter/neuromodulators. We also attempted to more fully characterized the factors responsible for the development of opiate-induced enhancements of naloxone's effects on LH. We found that this effect was produced only by those doses of morphine which initially suppressed serum LH levels, followed by a "rebound" increase in the gonadotropin 6-8 h later. A modest facilitation of LHRH-evoked increases in serum LH was also observed, but our data suggest that this represents only a minor component of opiate-induced enhancements of naloxone's effects. These data indicate that hypothalamic or suprahypothalamic sites are the major loci involved, but no differences in the uptake or regional distribution of naloxone in brain have been previously found, as a function of morphine pretreatment, nor were we able to demonstrate any alterations in opiate binding sites in the hypothalamus or whole brain. Thus, the mechanisms involved in this effect remain unclear.