The primary goals of this research project are 1) to gain a better understanding of the underlying mechanisms which mediate endogenous opioid inhibition of gonadotropin secretion and 2) to examine the physiological consequences of opioid suppression of gonadotropins, particularly luteinizing hormone (LH). Brain opioid peptides have been implicated in the regulation of LH secretion during the course of normal sexual maturation and the human menstrual cycle. Endogenous opioids appear to inhibit LH by blocking the release of hypothalamic gonadotropin-releasing hormone (GnRH) rather than by a direct action on the pituitary. However, little is known about which neuronal substrates mediate opioid effects on GnRH. Therefore, hypothalamic tissue will be perifused in vitro with opiate antagonists or agonists to confirm whether the major locus of opiate regulation of GnRH secretion is at the level of the GnRH nerve terminal in the median eminence or if the entire neuron is required. This perifusion system will also be used to examine whether interactions which are known to occur between opioids and adrenergic systems in regulating LH release take plaace in the hypothalamus. Opioids may also provide tonic inhibition of basal gonadotropin secretion. Therefore, a thorough examination will be made of endogenous rhythms in opioid regulation of basal gonadotropin secretion which were first identified in immature rats (Blank and Mann, 1981). Rats will be exposed to constant or varying conditions of lighting to determine if the observed diurnal pattern of serum LH responses to naloxone results from an endogenous rhythm and/or is cued by external environmental factors. Also, opioids may have direct implications for LH-dependent physiological events such as the timing of the onset of puberty. Thus, immature rats will be treated chronically with pellets and chimpanzees with osmotic minipumps containing opiate antagonists. In rats, the effects on the onset of puberty and postpubertal LH secretion will be investigated. In chimpanzees, the effects on developmental patterns of LH secretion (especially the juvenile period of inactive gonadotropin secretion) will be studied longitudinally. This project will not only enhance our understanding of normal physiological processes which subserve sexual maturation, but also will have potential value in developing therapies for hypogonadal states such as delayed puberty and amenorrhea.
| Blank, M S; Mann, D R; Daugherty, D T et al. (1986) Central, stereoselective receptors mediate the acute effects of opiate antagonists on luteinizing hormone secretion. Life Sci 39:1493-99 |
