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Male rats are more sensitive than female rats to the antinociceptive action of morphine. The present study used age-matched (9-10 weeks old) male and female Sprague-Dawley rats to investigate whether this difference is due to variation in micro-opioid receptor binding and G protein activation. In the warm-water tail-withdrawal assay at both 50 degrees C and 55 degrees C, morphine was 2-3 times more potent in males than females. In contrast, micro-opioid receptor number and the binding affinity of the micro-opioid agonists morphine and DAMGO in membranes from whole brain, cortex, thalamus, and spinal cord were not different between males and females. Similarly, morphine and DAMGO stimulation of G protein, determined using GTPase and [(35)S]GTPgammaS binding assays, did not show a difference between the sexes. The long-lasting micro-opioid receptor antagonist methocinnamox (0.32 mg/kg), given 24 h prior to morphine, reduced micro-opioid receptor number by approximately 50% in thalamic and spinal cord tissue from female and male rats and reduced the antinociceptive potency of morphine. Pretreatment of male rats with 0.32 mg/kg methocinnamox reduced the antinociceptive potency of morphine to that observed in female rats expressing a full complement of micro-opioid receptors. However, with increasing pretreatment doses of methocinnamox, the maximal antinociceptive effect of morphine was decreased in females but not males. The results suggest that pathways downstream of the micro-opioid receptor and G protein are more efficient in male rats than in female rats such that there is a larger receptor reserve for morphine-mediated antinociception.

N-methyl-D,L-aspartic acid (NMA), a potent neuroexcitatory and neurotoxic glutamic acid analogue, acutely elevated serum luteinizing hormone (LH) in male rats when given subcutaneously in doses below those that cause morphologically detectable hypothalamic neurotoxicity. NMA treatment in doses known to be subtoxic by morphological criteria fails to induce any permanent neuroendocrine dysfunction as assessed by several physiological parameters, including NMA responsiveness after multiple consecutive dosees spaced at 24 h intervals, subsequent basal LH levels and subsequent postcastration LH elevations. Like naloxone, NMA elevates serum LH by reversibly stimulating a central labile pool. Neither has a direct stimulatory effect on the pituitary in vitro. Treatment with either attenuates naloxone-induced LH stimulation 2 h, but not 14 days, later while pituitary responsiveness to LHRH in vivo remains unaltered. Neither NMA nor naloxone is dependent upon testosterone for its LH stimulatory action and both increase serum LH through physiological mechanisms responsive to testosterone inhibition. It is concluded that subtoxic LH stimulating doses of NMA provide a useful tool in discerning neurotransmitter systems involved in central control of the hypothalamic-pituitary-gonadal axis.

Previous research has indicated that endogenous opioids participate in the regulation of activity in the hypothalamic-pituitary-luteinizing hormone (LH) axis and mediate the negative feedback control exerted by testosterone. If this assumption is correct, then two predictions can be made. First, the effects of testosterone should be competitively inhibited by narcotic antagonists; and, second, opiates should mimic the acute and chronic effects of testosterone in the castrated male rat. The results of the present investigations support both of these predictions. We found that naloxone competitively antagonized the depressive effects of testosterone on serum LH in the castrated rat and, conversely, that testosterone competitively antagonized the LH-releasing properties of naloxone. In addition, morphine and testosterone both depressed serum LH levels in a dose-dependent fashion in the acutely castrated animal. Moreover, morphine was just as effective as testosterone in reversing the castration-induced fall in hypothalamic-LH-releasing hormone (LH-RH), which occurs in the chronically castrated male rat. On the other hand, morphine failed to reverse the long-term changes in pituitary LH content and increase in serum LH, which is consistent with prior observations that morphine affects only the hypothalamic aspect of the hypothalamic-pituitary-LH axis in the male rat. These results, thus, support the concept that an as yet unidentified opioid-containing neuronal system regulates activity in the hypothalamic-pituitary-LH axis and mediates the effects of testosterone on this axis.