ENDORPHINERGIC NEURONS AND CARDIOVASCULAR REGULATION

内啡肽神经元和心血管调节

• 批准号: 2225990
• 负责人: GEORGE KUNOS
• 金额: $ 14.46万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-14 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2225990
• 关键词: alpha adrenergic receptor; antihypertensive agents; baroreflex; cardiovascular function; clonidine; endogenous opioid; endorphins; gene expression; hypothalamus; in situ hybridization; laboratory rat; messenger RNA; molecular biology; neurons; neuropeptides; neuropharmacology; northern blottings; proopiomelanocortin; solitary tract nucleus

The endogenous opioid peptide, beta-endorphin, is present in the brain in neurons of the hypothalamic arcuate nucleus. The aim of the present application is to test whether a subset of endorphinergic neurons that project from the arcuate nucleus to the dorsal medullary nucleus of the solitary tract (NTS) is involved in cardiovascular regulation. Specifically, the first hypothesis to be tested is that these neurons may be activated by antihypertensive drugs acting at alpha2-adrenergic receptors in the arcuate nucleus, and that the resulting release of beta- endorphin and subsequent activation of opiate receptors in the NTS contributes to the hypotensive, bradycardic and baroreflex facilitatory effects of these drugs (e.g. alpha-methyldopa, clonidine). The second hypothesis to be tested is that the same endorphinergic neurons may be also involved in mediating the hypotension elicited by endotoxin treatment, as suggested by remarkable similarities between the opioid component in the hypotension induced by centrally acting alpha2-receptor agonists and in the hypotension associated with various forms of shock, including endotoxic shock. The experiments proposed will combine neuropharmacological and molecular biological approaches for testing these hypotheses in rats. In the first type of experiments we will examine whether alpha2-receptor agonists microinjected into the arcuate nucleus cause hypotension and bradycardia inhibited by alpha2-receptor antagonists injected into the same site. Furthermore, will test whether these effects, as well as the hypotension elicited by endotoxin treatment, can be inhibited by opiate antagonists or beta-endorphin antiserum microinjected into the ipsilateral NTS, or by surgical deafferentation of the NTS. The second type of experiment will explore the effects of chronic treatment of rats with alpha2-receptor agonists with and without antagonists, as well as chronic treatment with endotoxin, on the gene expression of the precursor of beta-endorphin, proopiomelanocortin (POMC), in the arcuate nucleus and its subregions. The level of neuropeptide mRNA in a neuron is considered a good indicator of the physiological activity of that neuron. The proposed experiments could provide new insight into mechanisms of antihypertensive drug action and into the mechanism of endogenous opioid involvement in the cardiovascular changes associated with certain forms of shock.

内源性阿片肽，β-内啡肽，存在于大脑中 存在于下丘脑弓状核的神经元中。 目前的目的 应用程序是测试内啡肽能神经元的子集是否 从弓状核投射到背髓核 孤束（NTS）参与心血管调节。 具体来说，要测试的第一个假设是这些神经元可能 被作用于α2-肾上腺素能的抗高血压药物激活 弓状核中的受体，以及由此产生的β- 内啡肽和随后 NTS 中阿片受体的激活 有助于低血压、心动过缓和压力反射促进 这些药物（例如α-甲基多巴、可乐定）的作用。 第二个 要测试的假设是相同的内啡肽能神经元可能是 还参与介导内毒素引起的低血压 治疗，正如阿片类药物之间的显着相似之处所表明的那样 中枢作用的α2受体引起的低血压的组成部分 激动剂和与各种形式的休克相关的低血压， 包括内毒素休克。 提议的实验将结合 神经药理学和分子生物学测试方法 这些假设是在老鼠身上进行的。 在第一类实验中，我们将 检查是否将α2受体激动剂显微注射到弓状体中 α2受体抑制核引起低血压和心动过缓 拮抗剂注射到同一部位。 此外，将测试是否 这些影响以及内毒素引起的低血压 治疗，可以被阿片拮抗剂或β-内啡肽抑制 将抗血清显微注射到同侧 NTS 中，或通过手术 NTS 的传入阻滞。 第二类实验将探索 α2受体激动剂长期治疗大鼠的效果 有或没有拮抗剂，以及长期治疗 内毒素，对β-内啡肽前体基因表达的影响， 阿黑皮素原 (POMC)，位于弓状核及其亚区域。 神经元中神经肽 mRNA 的水平被认为是一个很好的指标 该神经元的生理活动。 拟议的实验 可以为抗高血压药物作用机制提供新的见解 以及内源性阿片类药物参与的机制 与某些形式的休克相关的心血管变化。