Steroid Involvement in OFQ/N-Induced Prolactin Secretion

描述（由申请方提供）：待检验的假设是，对孤啡肽FQ/孤啡肽（OFQ/N）的催乳素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。具体而言，雌激素和/或孕酮调节OFQ/N诱导的催乳素分泌的作用，至少部分，下丘脑多巴胺能神经通路。将在卵巢切除（ovx）+/-类固醇替代的雌性Sprague-道利大鼠中进行OFQ/N催乳素分泌反应的剂量反应和时间过程研究。将通过HPLC/ECD测定动情间期雌性和雄性以及ovx +/-类固醇给药组中3种主要下丘脑多巴胺能神经系统对最小刺激剂量OFQ/N的反应。将审查反应的区域具体性。将通过定量这些相同动物的下丘脑孕酮能活性、5-羟色胺受体的药理学阻断和TRH免疫中和来确定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。假设TIDA神经元受到短暂的短暂抑制后，持续的催乳素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直接或用OP 4受体反义寡核苷酸预处理来证明。 我们的长期目标是了解阿片调节催乳素分泌的生理意义，特别是OFQ/N的作用及其通过卵巢类固醇的调节。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泌乳所必需的，而且在生殖过程中起着重要的作用。此外，它在介导应激反应、维持免疫活性甚至维持体内平衡方面也很重要。因为催乳素具有许多重要的生理作用，确定性腺类固醇激素在催乳素调节中的作用将为我们理解生理反应中性别差异所涉及的机制提供深入了解。为了了解生殖和压力相关的疾病，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，这对这种激素有强大的生理作用。

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.