The N-methyl-D-aspartate-mediated inhibitory control of gonadotropin-releasing hormone release in the hypothalamus of the adult male guinea pig is expressed through opioidergic systems.
Previously, we reported on a dual role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the control of GnRH secretion from the medial basal hypothalamus (MBH) of the adult male guinea pig, with a predominantly inhibitory action in the intact animal, which is reversed to a facilitatory role by orchidectomy. In the present study we examined the hypothesis that endogenous opioids are involved in the NMDA receptor-mediated inhibition of GnRH release. A static incubation system was used to test the effects of excitatory amino acid agonists and an excitatory amino acid antagonist, alone or in the presence of either the opiate agonist morphine or the mu-receptor antagonist naloxone, on in vitro GnRH release from the isolated MBH of intact, orchidectomized, or sham-operated guinea pigs. GnRH output from the MBH of intact guinea pigs was markedly suppressed in the presence of the NMDA-specific receptor agonist, N-methyl-D,L-aspartic acid (NMA; 50 mM), whereas NMDA-specific receptor blockade with D,L-amino-5-phosphonovaleric acid (AP-5; 1 mM) resulted in a pronounced facilitation of GnRH release, as did exposure to the non-NMDA-specific receptor agonist, kainic acid (50 mM). Opioidergic blockade with naloxone (1 mM) caused a reversal of the responses to NMA and AP-5, with exposure to these compounds this time resulting in clear facilitation and inhibition, respectively. The stimulatory action of kainic acid, on the other hand, remained unaffected by the presence of naloxone. Morphine inhibited basal GnRH output and also annulled the stimulatory effect of AP-5 on GnRH secretion. The results obtained from MBHs of sham-operated guinea pigs were identical to those seen for the intact animals, with naloxone effectively increasing baseline GnRH release and reversing the inhibitory effect of NMA and stimulatory action of AP-5 on GnRH secretion to a facilitation and inhibition, respectively. On the other hand, NMA caused a marked stimulation, whereas AP-5 produced a significant inhibition of GnRH release from the MBHs of orchidectomized guinea pigs; neither of these effects was altered by the presence of naloxone, which, moreover, had only a marginal effect on basal GnRH output in this group of animals. In conclusion, our present data provide evidence to support the view that the primary inhibitory action of NMDA receptor-mediated neurotransmission on GnRH release in the MBH of the intact male guinea pig is the result of activation of opioidergic systems and that a marked reduction of opioid tone after orchidectomy brings a facilitatory NMDA receptor-mediated system to the fore. On the other hand, non-NMDA-specific kainate receptor-mediated facilitation of GnRH, previously shown to be unaffected by gonadal status, appears to be also independent from opioidergic modulation.
Giri
M
M
Department of Endocrinology, University Hospital Ghent, Belgium.
Gao
C
C
Kaufman
J M
JM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D004723:Endorphins / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006168:Guinea Pigs; D007031:Hypothalamus / Q000378:metabolism*; D007033:Hypothalamus, Middle / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology / Q000502:physiology*; D009270:Naloxone / Q000494:pharmacology; D009919:Orchiectomy; D012737:Sex Factors
D004723:Endorphins; D007987:Gonadotropin-Releasing Hormone; D009270:Naloxone; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate