Hypothalamic opioid mechanisms in experimental uremic hypogonadism

Previous studies have demonstrated that abolition of the naloxone-stimulated increase in plasma LH levels is characteristic of hypothalamic dysfunction in experimental uremia. This study aimed to further characterize the nature of the defect in hypothalamic opiatergic mechanisms in experimental uremia. Specifically, we have tested the hypothesis that naloxone resistance was due to either opioid receptor dysfunction or diminished opioid peptide levels. Administration of naloxone (2 mg/kg, iv) to cannulated freely mobile rats confirmed previous observations that despite marked increases in plasma LH in control rats, plasma LH levels were unaffected in uremic male rats (P = 0.001 for group x time interaction). In a second experiment, morphine (2 mg/kg) or saline diluent was given quasi-continuously as small aliquots before each blood sample during the pulse studies of castrate mature male rats that had undergone either subtotal nephrectomy or sham operation. After the administration of morphine, uremic rats exhibited a 60% reduction in mean LH levels (14.9 +/- 1.4 vs. 6.0 +/- 0.7 ng/ml) attributable to a 42% reduction in LH pulse frequency (3.6 +/- 0.4 vs. 2.1 +/- 0.5 peaks/3 h) and a 60% reduction in LH pulse amplitude (4.7 +/- 0.5 vs. 1.9 +/- 0.3 ng/ml). The preservation of sensitivity to morphine despite complete naloxone resistance raised the alternate hypothesis of depletion of endogenous opiate peptide levels in the uremic hypothalamus. This hypothesis was tested by measuring the beta-endorphin content of the medial basal hypothalamus (MBH) in a rat beta-endorphin RIA. Rat MBH beta-endorphin content was not significantly altered specifically by either uremia or castration. We conclude, therefore, that naloxone resistance of plasma LH in experimental uremia is not due to either defects in opioid receptor function or reduced hypothalamic beta-endorphin content. Instead, we suggest that uremia may diminish the release of endogenous opioid peptides that interact with GnRH neurons from the MBH.