Mechanisms of CNS Autonomic Regulation by Acupuncture

 描述（由申请人提供）：我们正在研究针灸调节心血管功能的机制，重点是其对血压升高（BP）的调节。电针能够降低血压的急性和慢性升高，并减轻由需求引起的心肌缺血。针灸的作用起效缓慢，但作用时间延长。我们以前曾获得资助，研究针灸对心血管作用的神经机制。虽然这些研究表明，EA和手针刺（MA）在穴位覆盖躯体传入神经减弱心血管交感神经兴奋性反应，各种形式的针灸应用激活感觉神经纤维降低血压升高的机制在很大程度上是未知的。在这方面，虽然EA和MA通过电和机械刺激激活感觉神经，但尚不清楚这些方式是否通过通道中纤维的直接去极化或通过由受体特异性机制介导的化学中间体（例如瞬时受体电位香草酸1型（TRPV 1）或ATP嘌呤能受体）刺激感觉传入神经及其背根神经节中的胞体。我们的研究还表明，刺激感觉神经后，EA通过阿片类药物通过调节延髓头端腹外侧区（rVLM）的前交感神经活动来降低BP的反射升高，该脑干核团重要地控制交感神经流出并因此控制心血管功能。然而，目前尚不清楚阿片类药物是否单独作用或介导其他心血管抑制神经调节剂如腺苷或γ-氨基丁酸（GABA）的作用，以促进针灸在降低心血管兴奋性反应期间升高的血压以及持续高血压中的作用。此外，没有关于阿片类药物和其他神经递质在降低血压升高中的作用的信息，这些作用是在身体穴位以外的位置进行针灸，如耳针（AA）。在这方面，在耳朵中的“心脏点”处施加的手动和电AA（其类似于激活投射到髓质的迷走传入神经）被经验性地用于管理升高的BP。然而，骨髓机制AA的肿胀行动仍然未知。本申请的中心假设是，通过阿片样物质介导的机制，通过刺激感觉受体（MA）或通道中的细纤维轴突（EA），通过调节rVLM前交感神经活性，在躯体和颅迷走神经穴位处针刺降低升高的BP。本基金主要研究4个新领域：1）电针和MA抑制心血管功能的电和机械-化学感觉神经机制; 2）rVLM腺苷在阿片介导针刺抑制兴奋性心血管反射反应中的作用; 3）针刺通过脑啡肽和腺苷降低持续性高血压患者的血压;耳针通过阿片和GABA调节血压升高的延髓机制。将在与高血压和交感神经功能亢进患者高度相关的拟议研究中使用解剖学、生物化学、生理学、电生理学、药理学和分子方法，这些患者有可能从临床针灸中受益。

 DESCRIPTION (provided by applicant): We are investigating mechanisms by which acupuncture regulates cardiovascular function, focusing on its modulation of elevated blood pressure (BP). Electroacupuncture (EA) is capable of lowering acute and chronic elevations in BP and alleviating demand-induced myocardial ischemia. Acupuncture's actions are slow in onset, but the duration of action is prolonged. We have been funded previously to study neural mechanisms underlying acupuncture's cardiovascular effects. Although these studies have shown that both EA and manual acupuncture (MA) applied at acupoints overlying somatic afferent nerves attenuate cardiovascular sympathoexcitatory responses, the mechanisms by which various forms of acupuncture application activate sensory nerve fibers to lower elevated BP are largely unknown. In this regard, although EA and MA activate sensory nerves through electrical and mechanical stimulation, it is unclear whether these modalities stimulate sensory afferent nerves and their perikarya in dorsal root ganglia through direct depolarization of fibers in passage or through a chemical intermediate mediated by a receptor specific mechanism, such as transient receptor potential vanilloid type-1 (TRPV1) or ATP purinergic receptors. Our studies also have demonstrated that, following stimulation of sensory nerves, EA lowers reflex elevations in BP through opioids by modulating presympathetic activity in the rostral ventrolateral medulla (rVLM), a brain stem nucleus that importantly controls sympathetic outflow and hence cardiovascular function. However, it is unclear if opioids act alone or mediate the actions of other cardiovascular-suppressing neuromodulators like adenosine or γ-amino butyric acid (GABA) to facilitate the action of acupuncture in lowering elevated BP during cardiovascular excitatory responses as well in sustained hypertension. Additionally, there is no information available on the role of opioids and other neurotransmitters in lowering elevated BP with acupuncture applied at locations other than somatic acupoints, like auricular acupuncture (AA). In this respect, manual and electrical AA applied at "the heart point" in the ear, which likey activates vagal afferent nerves projecting to the medulla, is used empirically to manage elevated BP. However, medullary mechanisms underlying AA's hypotensive actions remain unknown. The central hypothesis of this application is that acupuncture at somatic and cranial vagal nerve acupoints lowers elevated BP by modulating rVLM presympathetic activity through opioid- mediated mechanisms, by stimulating sensory receptors (MA) or thin fiber axons in passage (EA). The present grant focuses on four new areas: 1) electrical and mechanical-chemical sensory neural mechanisms by which EA and MA inhibit cardiovascular function; 2) the role of rVLM adenosine in opioid mediation of acupuncture inhibition of excitatory cardiovascular reflex responses; 3) acupuncture's action in lowering BP in sustained hypertension through medullary enkephalins and adenosine and 4) medullary mechanisms of auricular acupuncture in modulating elevated BP through actions of opioids and GABA. Anatomical, biochemical, physiological, electrophysiological, pharmacological and molecular approaches will be used in the proposed studies that are highly relevant to patients with hypertension and sympathetic hyperactivity, who have the potential to benefit from clinical acupuncture.