Mechanims of CNS Autonomic Regulation by EA

说明（由申请人提供）：针灸及其有效的替代疗法，电针（EA），是公认的治疗疼痛，恶心和呕吐的方法。小型试验进一步表明，EA可以降低血压升高。在过去的两个资助周期中进行的研究已经评估了EA降低交感神经流出和血压升高的能力的脊髓上机制。针刺与非特异性体交感刺激的区别在于其穴位的相对特异性和作用时间的延长。我们最近证明，在心包和胃经的低频、低强度EA中，特别是在P5-P6和St36-St37处，点特异性血压调节的效果最大，因为这些穴位组为吻侧腹外侧髓质（rVLM）的运动前交感神经元提供了重要的输入。我们还证明，阿片类物质，特别是内啡肽、脑啡肽、伤害肽和氨基丁酸（GABA），介导了EA相关的初始抑制，而阿片类物质和GABA则是EA对血压的长期调节的基础。EA在突触前和突触后作用于rVLM谷氨酸释放，以降低交感神经流出。这一更新扩展了我们的研究，以探讨通过脊髓背角和中外侧柱中dynorphin和nociceptin的作用，EA节段性调节血压升高。此外，我们最近已经开始探索针灸在两种反射性血管抑制模型中提高抑郁血压的潜力。第一种方法是在氯氯糖麻醉的猫体内使用苯双胍（PBG）刺激5-羟色胺-3 （5- ht3）心肺受体，通过内侧孤束核（mNTS）和双核（NA）的通路反射性降低心率和血压。第二种涉及氯胺酮-二嗪麻醉大鼠轻度胃胀时的反射性心血管抑制，这似乎通过GABAA机制抑制NA的前神经和rVLM的前交感神经，可能起源于尾侧腹外侧髓质（cVLM）。初步数据表明，EA通过PBG刺激时mNTS、中缝白核和NA中的GABA能、5-羟色胺或阿片能机制，以及胃膨胀时cVLM和NA中的GABA调节这些降压药反射。其他具有重要临床意义的研究将探讨两组穴位结合的刺激方式和潜在机制，包括穴位特异性、频率调制和空间求和。进一步了解针灸通过其脊柱和棘上作用使血压正常化的能力，以及潜在的机制，将为针灸在血压升高或抑郁的情况下的临床应用提供重要的线索，并将有助于西方医学和科学界对这种治疗技术的接受程度的提高。血压异常是冠状动脉疾病、中风、充血性心力衰竭和晕厥的主要危险因素。然而，高血压和低血压的治疗都很差，因为许多患者往往不愿意使用标准的药物治疗。如今，在美国，越来越多的患者正在寻找更容易接受的综合疗法来治疗他们的血压异常。虽然针灸可能是一种可行的、廉价的、副作用发生率极低的替代疗法，但医生通常不愿推荐这种疗法，因为关于其疗效的数据很少，尤其是关于其作用机制的数据。目前的应用将为针灸治疗高血压或低血压的疗效和作用机制提供重要的新信息。

DESCRIPTION (provided by applicant): Acupuncture and its potent alternative, electroacupuncture (EA), are accepted treatments for pain, nausea and vomiting. Small trails further suggest that EA can lower elevated blood pressure. Studies conducted in the last two grant cycles have evaluated supra-spinal mechanisms underlying EA's ability to reduce elevated sympathetic outflow and blood pressure. Acupuncture is differentiated from non-specific somatosympathetic stimulation by its relative point specificity and its prolonged action. We recently demonstrated point specific blood pressure modulation with the largest effect occurring during low frequency, low intensity EA at the pericardial and stomach meridians, specifically at P5-P6 and St36-St37, since these sets of acupoints provide significant input to premotor sympathetic neurons in the rostral ventrolateral medulla (rVLM). We also have demonstrated that opioids, specifically endorphins and enkephalin, nociceptin and (-amino butyric acid (GABA), mediate the initial EA-related inhibition while opioids and GABA underlie prolonged modulation of blood pressure by EA. EA works both pre- and post- synaptically on rVLM glutamate release, to lower sympathetic outflow. This renewal extends our studies to investigate EA segmental regulation of elevated blood pressure through actions involving dynorphin and nociceptin in the spinal cord dorsal horn and intermediolateral columns. In addition, we recently have begun to explore the potential for acupuncture to elevate depressed blood pressure in two models of reflex vasodepression. The first uses phenylbiguanide (PBG) in chloralose anesthetized cats to stimulate 5- hydroxytryptamine-3 (5-HT3) cardiopulmonary receptors to reflexly lower heart rate and blood pressure through pathways in the medial nucleus tractus solitarii (mNTS) and nucleus ambiguus (NA). The second involves reflex cardiovascular depression during mild gastric distension in ketamine-xylazine anesthetized rats, which appears to inhibit the prevagal neurons in the NA and presympathetic neurons in the rVLM through a GABAA mechanism, likely originating from the caudal ventrolateral medulla (cVLM). Preliminary data suggest that EA modulates these cardiodepressor reflexes through GABAergic, 5-HT or opioidergic mechanisms in the mNTS, nucleus raphe pallidus and NA during PBG stimulation and through GABA in the cVLM and NA during gastric distension. Additional studies, which have important clinical implications, will investigate stimulation modality and the underlying mechanisms, including point specificity, frequency modulation and spatial summation by combining two sets of acupoints. An improved understanding of acupuncture's ability to normalize blood pressure through its spinal and supraspinal actions, as well as underlying mechanisms, will provide important clues that can assist in the clinical use of acupuncture in conditions of either elevated or depressed blood pressure and will contribute to increased acceptance of this therapeutic technique by the western medical and scientific communities. PUBLIC HEALTH RELEVANCE: Project Narrative Blood pressure abnormalities are major risk factors for coronary artery disease, stroke, congestive heart failure and syncope. However, both hypertension and hypotension are poorly treated because many patients often are unwilling to use standard medical therapy. Today in the US, patients increasingly are looking for integrative therapies that are more acceptable for treatment of their blood pressure abnormality. Although acupuncture may be a viable inexpensive alternative that has a very low incidence of side effects, physicians generally are reluctant to recommend this therapy because little data are available on its efficacy and particularly on its mechanisms of action. The current application will provide important new information on both efficacy and mechanism of action in acupuncture treatment of either elevated or low blood pressure.