ENDORPHINERGIC NEURONS AND CARDIOVASCULAR REGULATION

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。现在的目的是 应用是测试内啡肽能神经元的一个子集是否 从弓状核至延髓背核的投射 孤束(NTS)参与心血管调节。 具体地说，要检验的第一个假设是，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，由此产生的β-受体释放 内啡肽与孤束核阿片受体的激活 有助于降压、心动过缓和压力感受器反射易化 这些药物(如α-甲基多巴、可乐定)的效果。第二 有待检验的假设是，相同的内啡肽能神经元可能是 也参与了内毒素所致低血压的调节 治疗，从阿片类药物之间惊人的相似之处来看 中枢作用的α2受体所致低血压的成分 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。拟议中的实验将结合 神经药理学和分子生物学检测方法 这些假说在老鼠身上。在第一类实验中，我们将 检查α2受体激动剂是否微量注射到弓状体内 核团引起低血压和心动过缓被α2受体抑制 将拮抗剂注射到同一部位。此外，还将测试是否 这些影响以及内毒素引起的低血压 治疗，可被阿片类拮抗剂或β-内啡肽抑制 同侧NTS内微量注射抗血清或外科手术 NTS的去传入。第二类实验将探索 α2受体激动剂慢性给药对大鼠的影响 使用和不使用拮抗剂，以及长期使用 内毒素，对β-内啡肽前体基因表达的影响， 原阿片黑素皮质素(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 该神经元的生理活动。拟议中的实验 可以为抗高血压药物的作用机制提供新的见解 并探讨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。

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.