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 在下丘脑弓状核的神经元中。 目前的目标是 应用程序是测试是否内啡肽能神经元的子集， 从弓状核投射到背髓核， 孤束（NTS）参与心血管调节。 具体来说，第一个要检验的假设是，这些神经元可能 被作用于α 2-肾上腺素能的抗高血压药物激活 在弓状核的受体，并由此产生的释放β- 内啡肽和随后激活NTS中的阿片受体 有助于呼吸，心动过缓和压力反射促进 这些药物（如α-甲基多巴、可乐定）的作用。 第二 有待检验的假设是，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性所表明的那样， 中枢作用α 2受体引起的低血压中的成分 激动剂和与各种形式休克相关的低血压， 包括内毒素休克 所提出的实验将联合收割机 神经药理学和分子生物学方法 这些假设在老鼠身上。 在第一种实验中，我们将 检查是否有α 2受体激动剂微量注射到弓形 α 2-受体抑制核引起的低血压和心动过缓 注射到同一部位的拮抗剂。 此外，将测试是否 这些效应以及内毒素引起的低血压 治疗，可以抑制阿片拮抗剂或β-内啡肽 将抗血清显微注射到同侧NTS中，或通过手术 NTS的传入神经阻滞。 第二类实验将探索 α 2受体激动剂对大鼠长期治疗的影响 有和没有拮抗剂，以及长期治疗， 内毒素对β-内啡肽前体基因表达的影响， 前阿黑皮素（POMC），在弓状核及其亚区。 神经元中神经肽mRNA的水平被认为是一个很好的指标 神经元的生理活动。 拟议的实验 可能为抗高血压药物的作用机制提供新的见解 并进入内源性阿片类药物参与的机制， 与某些形式的休克有关的心血管变化。