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 i dentifies 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-B (02))
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Thrasher, Terry N
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University of California Irvine
Internal Medicine/Medicine
Schools of Medicine
United States
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Longhurst, John C; Tjen-A-Looi, Stephanie C (2017) Evidence-based blood pressure reducing actions of electroacupuncture: mechanisms and clinical application. Sheng Li Xue Bao 69:587-597
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Fu, Liang-Wu et al. (2016) Paraventricular Nucleus Modulates Excitatory Cardiovascular Reflexes during Electroacupuncture. Sci Rep 6:25910
Li, Min; Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling et al. (2016) Repetitive Electroacupuncture Attenuates Cold-Induced Hypertension through Enkephalin in the Rostral Ventral Lateral Medulla. Sci Rep 6:35791
Cheng, Ling; Li, Peng; Tjen-A-Looi, Stephanie Cheeyee et al. (2015) What do we understand from clinical and mechanistic studies on acupuncture treatment for hypertension? Chin Med 10:36
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Longhurst, John C (2014) GABA in nucleus tractus solitarius participates in electroacupuncture modulation of cardiopulmonary bradycardia reflex. Am J Physiol Regul Integr Comp Physiol 307:R1313-23
Li, Min; Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling et al. (2013) Electroacupuncture modulation of reflex hypertension in rats: role of cholecystokinin octapeptide. Am J Physiol Regul Integr Comp Physiol 305:R404-13
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Li, Min et al. (2013) Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats. Am J Physiol Regul Integr Comp Physiol 304:R321-32
Longhurst, John C; Tjen-A-Looi, Stephanie (2013) Acupuncture regulation of blood pressure: two decades of research. Int Rev Neurobiol 111:257-71
Tjen-A-Looi, Stephanie C; Li, Peng; Li, Min et al. (2012) Modulation of cardiopulmonary depressor reflex in nucleus ambiguus by electroacupuncture: roles of opioids and ?-aminobutyric acid. Am J Physiol Regul Integr Comp Physiol 302:R833-44
Li, Min; Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling et al. (2012) Repetitive electroacupuncture causes prolonged increased met-enkephalin expression in the rVLM of conscious rats. Auton Neurosci 170:30-5

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