Neural Substrates of EA in Cardiovascular Control

描述(申请人提供)：针灸是一种古老的治疗方式，其作用机制直到最近才被确定。虽然临床试验确定了对疼痛、感染和心血管疾病(包括高血压、心肌缺血和心律失常)的疗效，但很明显，我们对其作用机制知之甚少。在过去的三年里，这项资助探索了一条长环路的功能，包括下丘脑腹侧的弓状核(ARC)、中脑的中脑导水管周围灰质(VIPAG)和延髓吻侧腹外侧区(RVLM)在调节内脏交感神经兴奋反射中的功能。我们已经证实了位于正中神经远端和腓深躯体神经的穴位在电针(EA)时被激活到ARC、VIPAG和RVLM的兴奋性输入。ARC向VIPAG提供兴奋性投射，VIPAG向RVLM提供抑制性投射，最终调节支配脊髓交感神经流出到心血管系统的交感前神经元。这笔赠款以三个具体目标完善和扩展了我们先前的观察结果。第一个目的是评估ARC和vIPAG之间相互投射的意义，我们假设这加强了在电针过程中来自躯体传入刺激的ARC的输入。第二个目的是确定特定的神经递质系统的作用，包括ARC和vIPAG中的谷氨酸及其离子亲电受体，ARC中的乙酰胆碱和vIPAG中的内源性大麻素系统，我们假设这些系统可以抑制γ-氨基丁酸的释放，从而抑制vIPAG神经元的活动，并最终加强vIPAG对RVLM的抑制。第三个目的是研究延髓中线核的作用，特别是中缝暗核、大核和苍白球，我们认为这些核接受来自vIPAG的兴奋性输入，并反过来抑制RVLM的活动。研究将使用解剖学、细胞电生理学、药理学、微量采集微量分析和整个动物反射方法的组合来检验这些假说。这些增加的知识将使医生和科学家对电针对心血管的影响有更好的机械性理解，这将增加它在临床上的接受度，例如在心血管疾病患者中。此外，了解针灸的机制基础可能会使医生能够优化临床心血管反应的治疗。

DESCRIPTION (provided by applicant): Acupuncture is an ancient therapeutic modality whose mechanisms of action only recently are being defined. While clinical trials are defining efficacy in areas such as pain, infections and cardiovascular disease, including hypertension, myocardial ischemia and arrhythmias, it is clear that we know little about its mechanisms of action. Over the last three year, this grant has explored the function of a long-loop pathway, including the arcuate nucleus (ARC) in the ventral hypothalamus, the ventrolateral periaqueductal gray (vIPAG) in the midbrain and the rostral ventrolateral medulla (rVLM) in regulation of visceral sympathoexcitatory reflexes. We have demonstrated excitatory input from acupuncture points located along the distal median and deep peroneal somatic nerves activated during electroacupuncture (EA) to the ARC, vIPAG and rVLM. The ARC provides an excitatory projection to the vIPAG, which in turn, provides an inhibitory projection to the rVLM that ultimately regulates sympathetic premotor neurons that innervate the spinal cord sympathetic outflow to the cardiovascular system. The present grant refines and extends our previous observations with three specific aims. The first aim evaluates the significance of reciprocal projections between the ARC and the vIPAG, which we hypothesize, reinforces input in the ARC from somatic afferent stimulation during EA. The second aim identifies the role of specific neurotransmitter systems, including glutamate and its ionotropic receptors in ARC and vIPAG, acetylcholine in ARC and the endocannabinoid system in vIPAG, which we hypothesize, inhibits the release of gamma-aminobutyric acid to disinhibit vIPAG neuronal activity and ultimately potentiate vIPAG inhibition of the rVLM. The third aim examines the role of midline medullary nuclei, especially the nuclei raphe obscurus, magnus and pallidus, which we believe receive excitatory input from the vIPAG and, in turn, inhibit rVLM activity. Studies will use a combination of anatomical, cellular electrophysiological, pharmacological, microcollection-microassay and whole animal reflex approaches to test these hypotheses. This added knowledge will provide physicians and scientists with a greater mechanistic understanding of EA's cardiovascular influence, which will increase its clinical acceptance, e.g., in patients with cardiovascular disease. Furthermore, knowledge of the mechanistic basis of acupuncture may allow practitioners to optimize the clinical cardiovascular responses to treatment.