Steroid Involvement in OFQ/N-Induced Prolactin Secretion

描述(由申请人提供)：需要检验的假设是，催乳素对孤儿FQ/Nociceptin(OFQ/N)的分泌反应的性别差异是由于卵巢类固醇激素的神经调节作用。具体地说，雌激素和/或孕酮通过至少部分作用于下丘脑多巴胺能神经通路来调节OFQ/N诱导的催乳素的分泌。将在卵巢切除(OVX)/非类固醇替代雌性SD大鼠身上进行催乳素对OFQ/N的分泌反应的剂量反应和时间过程研究。发情期女性和男性以及OVX/-类固醇治疗组的下丘脑、多巴胺能三大神经系统对最小刺激量OFQ/N的反应将通过高效液相/电子捕获检测器测定。将检查反应的地区特异性。5-羟色胺和促甲状腺激素释放激素(TRH)在维持催乳素反应中的作用将通过定量这些动物的下丘脑5-羟色胺能活动、5-羟色胺受体的药理阻断和TRH免疫中和作用来确定。假说是，在短暂、短暂地抑制TIDA神经元之后，催乳素的持续增加是由于释放因子，即5-羟色胺和/或TRH。最后，OFQ/N作用的特异性将通过药理学或OP4受体反义寡核苷酸的预处理来证实。 我们的长期目标是了解阿片类药物对催乳素分泌的生理意义，特别是OFQ/N的作用以及卵巢类固醇对其调节。催乳素是一种重要的垂体前叶激素，具有300多种不同的生物活性。催乳素不仅是哺乳动物哺乳所必需的，而且在繁殖过程中还扮演着其他重要的角色。此外，它在调节应激反应、维持免疫活性、甚至维持体内平衡方面也很重要。由于催乳素具有众多重要的生理作用，因此，研究性腺激素在催乳素调节中的作用将有助于我们理解生理反应中性别差异的机制。要了解生殖和应激相关的疾病，重要的是要了解催乳素分泌的调节，包括内源性阿片类药物的控制，内源性阿片类药物对这种激素具有强大的生理影响。

DESCRIPTION (provided by applicant): The hypothesis to be tested is that the gender difference in the prolactin secretory response to Orphanin FQ/Nociceptin (OFQ/N) is due to neuromodulatory effects of the ovarian steroid hormones. Specifically, estrogen and/or progesterone modulate OFQ/N-induced prolactin secretion by acting, at least in part, on hypothalamic dopaminergic neural pathways. Dose response and time course studies of the prolactin secretory response to OFQ/N will be performed in ovariectomized (ovx) +/- steroid replaced female Sprague- Dawley rats. The response of the 3 major hypothalamic, dopaminergic neural systems to a minimum stimulatory dose of OFQ/N will be determined by HPLC/ECD in diestrous females and males and in the ovx +/- steroid treated groups. Regional specificity of the response will be examined. The role of serotonin and Thyrotropin Releasing Hormone (TRH) in sustaining the prolactin response will be determined by quantifying hypothalamic serotonergic activity in these same animals, by pharmacological blockade of serotonin receptors and by TRH immunoneutralization. The hypothesis is that following a brief, transient inhibition of the TIDA neurons, the sustained prolactin increase is due to releasing factors, i.e. serotonin and/or TRH. Finally, specificity of OFQ/N action will be demonstrated pharmacologically or by pretreatment with OP4 receptor antisense oligonucleotides. Our long-term objective is to understand the physiological significance of opiate regulation of prolactin secretion, particularly the role of OFQ/N and its modulation by ovarian steroids. Prolactin is an important anterior pituitary hormone that has over 300 separate biological activities. Prolactin is not only necessary for lactation in mammals, but also plays other, important roles in reproduction. Furthermore, it is important in mediating the stress response, maintaining immunocompetence and even maintaining homeostasis. Because prolactin has numerous, important physiological effects, determining the role of gonadal steroids in prolactin regulation will provide insight into our understanding of the mechanisms involved in the gender differences in physiological responses. To understand reproductive and stress-related disorders, it is important to understand the regulation of prolactin secretion, including control by the endogenous opiates, which have potent, physiological effects on this hormone.