Mechanisms of CNS Autonomic Regulation by Acupuncture

 描述(申请人提供)：我们正在研究针灸调节心血管功能的机制，重点是它对血压升高的调节。电针(EA)能够降低急性和慢性血压升高，缓解需求诱导的心肌缺血。针灸起效较慢，但作用时间较长。我们之前曾被资助研究针灸心血管效应的神经机制。虽然这些研究表明，电针和手法针刺(MA)都能减弱躯体传入神经上方的穴位，但不同形式的针刺激活感觉神经纤维降低血压升高的机制尚不清楚。在这一点上，尽管电针和机械刺激通过电刺激和机械刺激来激活感觉神经，但目前尚不清楚这些方式是通过通路中的纤维直接去极化还是通过受体特异性机制介导的化学中间体来刺激背根神经节的感觉神经传入神经和它们的核周膜，如瞬时受体电位香草样物质-1(TRPV1)或三磷酸腺苷能受体。我们的研究还表明，在刺激感觉神经后，电针通过阿片类药物调节头端延髓腹外侧区(RVLM)的交感前活动，从而降低BP的反射性升高。RVLM是一个脑干核团，重要地控制交感神经流出，从而控制心血管功能。然而，目前尚不清楚阿片类药物是单独作用还是介导其他心血管抑制神经调节剂的作用，如腺苷或γ-氨基丁酸，以促进针刺在心血管兴奋反应期间降低血压的作用，以及在持续性高血压中。此外，目前还没有关于阿片类药物和其他神经递质在体穴以外的位置应用针灸降低血压升高的作用的信息，如耳针(AA)。在这方面，在耳朵的“心点”应用手动和电动AA，类似于激活投射到延髓的迷走传入神经，经验性地用于控制血压升高。然而，AA的降压作用背后的髓质机制仍不清楚。这一应用的中心假设是，针刺躯体和脑迷走神经穴位可以通过阿片介导的机制调节RVLM前交感神经活动，通过刺激感觉受体(MA)或通道中的细纤维轴突(EA)来降低升高的血压。目前的拨款集中在四个新领域：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腺苷在阿片类药物介导针刺抑制兴奋性心血管反射反应中的作用；3)针刺通过延髓脑啡肽和腺苷降低持续性高血压患者血压的作用；4)耳针通过阿片类药物和GABA作用调节血压升高的延髓机制。拟议的研究将使用解剖学、生化、生理学、电生理学、药理学和分子学方法，这些方法与高血压和交感神经多动患者高度相关，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.