INHIBITION OF DYNORPHIN STIMULATED ACTH RELEASE

抑制强啡肽刺激的 ACTH 释放

• 批准号: 2897779
• 负责人: ALEXANDER V BIRK
• 金额: $ 1.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2897779
• 关键词: adrenocorticotropic hormone; calcium channel; corticosteroid receptors; cyclic GMP; dexamethasone; dynorphins; glucocorticoids; guanylate cyclase; hormone biosynthesis; hormone regulation /control mechanism; pituitary gland; potassium channel; radioimmunoassay; tissue /cell culture; voltage /patch clamp

DESCRIPTION: (Applicant's Abstract) The main goal of this proposal is to study the cellular mechanism of the early inhibitory effect of glucocorticoids on Dynorphin-stimulated ACTH release. To accomplish this goal, three specific aims were established: (1) to determine if glucocorticoids inhibit Dynorphin-stimulated ACTH release acting directly on corticotrophs of anterior pituitary. This will be accomplished by determing the effects of dexamethasone on Dynorphin-stimulated ACTH secretion from mouse anterior pituitary tumor cells. (2) to test if glucocorticoid inhibitory action is mediated via glucocorticoid type II receptors and activation of guanylyl cyclase. Glucocorticoid type II receptor antagonists RU28362 and RU26988 will be used to study their effect on dexamethasone inhibitory action. To test the role of cGMP, dexamethasone-stimulated cGMP formation will be determined, followed by the use of the guanylyl cyclase inhibitor LY83583 and Br-8-cGMP to see the importance of cGMP in inhibition Dynorphin-stimulated ACTH release. (3) to study a role of voltage-dependent calcium channels and calcium-dependent potassium channels in glucocorticoids inhibitory action on Dynorphin-stimulated ACTH release. Whole cell perforated patch-clamp will be used to study any changes in dexamethasone stimulated calcium and potassium currents. In addition, specific inhibitors of voltage-dependent calcium currents and calcium-dependent potassium currents will be used to study their effects on dexamethasone inhibition of Dynorphin-stimulated ACTH release. An understanding of the regulatory control Dynorphin-stimulated ACTH secretion is important, because Dynorphin has been shown to inhibit the development of tolerance to opioids to eliminated the development of sensitization to cocaine, thus making it a good drug for treatment of drug abuse.

描述：（申请人摘要） 该提案的主要目标是研究细胞机制 糖皮质激素对强啡肽刺激的 ACTH 的早期抑制作用 发布。 为了实现这一目标，制定了三个具体目标： (1)确定糖皮质激素是否抑制强啡肽刺激的ACTH 释放直接作用于垂体前叶的促肾上腺皮质激素。 这将 通过确定地塞米松的作用来完成 强啡肽刺激小鼠垂体前叶瘤分泌 ACTH 细胞。 (2) 测试糖皮质激素的抑制作用是否通过以下途径介导 糖皮质激素 II 型受体和鸟苷酸环化酶的激活。 将使用糖皮质激素II型受体拮抗剂RU28362和RU26988 研究它们对地塞米松抑制作用的影响。 测试角色 cGMP，地塞米松刺激的 cGMP 形成将被确定， 随后使用鸟苷酸环化酶抑制剂LY83583和Br-8-cGMP 了解 cGMP 在抑制强啡肽刺激的 ACTH 中的重要性 发布。 (3) 研究电压依赖性钙通道的作用和 钙依赖性钾通道对糖皮质激素的抑制作用 强啡肽刺激 ACTH 释放。 全细胞穿孔膜片钳将 用于研究地塞米松刺激的钙和 钾电流。 此外，电压依赖性的特异性抑制剂 钙电流和钙依赖性钾电流将用于 研究它们对地塞米松抑制强啡肽刺激的 ACTH 的影响 发布。 了解强啡肽刺激的调节控制 ACTH 的分泌很重要，因为强啡肽已被证明可以抑制 发展对阿片类药物的耐受性，以消除 对可卡因过敏，从而使其成为治疗毒品的良好药物 虐待。