Mechanims of CNS Autonomic Regulation by EA

描述（由申请人提供）：针灸及其有效的替代品，电针（EA），是公认的治疗疼痛，恶心和呕吐。小试验进一步表明，EA可以降低血压升高。在过去的两个资助周期进行的研究已经评估了超脊髓机制的基础EA的能力，以减少升高的交感神经流出和血压。针刺与非特异性躯体交感神经刺激的区别在于其相对的穴位特异性和作用时间的延长。我们最近证明了点特定的血压调制与最大的影响发生在低频率，低强度EA在心包和胃的经络，特别是在P5-P6和St 36-St 37，因为这些组的穴位提供了显着的输入到运动前交感神经元在延髓头端腹外侧（rVLM）。我们也已经证明，阿片类药物，特别是内啡肽和脑啡肽，痛敏素和β-氨基丁酸（GABA），介导的初始EA相关的抑制，而阿片类药物和GABA的基础上延长调制的血压EA。电针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EA节段性调节血压升高，通过涉及脊髓背角和中间外侧柱的强啡肽和痛敏素的行动。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升高血压的潜力。第一种是在氯醛糖麻醉的猫中使用苯基双胍（PBG）来刺激5-羟色胺-3（5-HT 3）心肺受体，以通过内侧孤束核（mNTS）和疑核（NA）中的通路反射性地降低心率和血压。第二个涉及氯胺酮-甲苯噻嗪麻醉大鼠轻度胃扩张期间的反射性心血管抑制，其似乎通过GABAA机制抑制NA中的迷走神经前神经元和rVLM中的前交感神经元，可能源自尾侧腹外侧髓质（cVLM）。初步数据表明，EA调节这些心脏降压反射通过GABA能，5-HT或阿片类药物的机制，在mNTS，中缝苍白核和NA在PBG刺激和通过GABA的cVLM和NA在胃扩张。具有重要临床意义的其他研究将研究刺激方式和潜在机制，包括结合两组穴位的点特异性，频率调制和空间总和。对针灸通过其脊柱和脊髓上作用使血压正常化的能力以及潜在机制的进一步了解，将提供重要的线索，可以帮助针灸在血压升高或降低的情况下的临床应用，并将有助于增加西方医学和科学界对这种治疗技术的接受。公共卫生相关性：血压异常是冠心病、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，因为许多患者通常不愿意使用标准的药物治疗。今天，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替代品，副作用的发生率非常低，但医生通常不愿意推荐这种疗法，因为关于其疗效，特别是其作用机制的数据很少。目前的应用将为针灸治疗血压升高或降低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.