Effects of Acupuncture-Induced nNOS-NO in Dorsal Medulla on Sensory Neuropathy

针刺诱导背髓质 nNOS-NO 对感觉神经病变的影响

基本信息

批准号：
7752813
负责人：
SHENG-XING MA
金额：
$ 18.82万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752813
关键词：
Absence of pain sensation Acupuncture Points Acupuncture Therapy Acupuncture procedure Address Affect Aminobutyric Acids Analgesics Anesthesia and Analgesia Arginine Biochemical Biological Assay Brain Brain Stem Cell Nucleus Cerebral Ventricles Chemicals Chinese Traditional Medicine Chronic Clinical Cutaneous Cyclic GMP Depressed mood Diabetic Neuropathies Disease Distress Dorsal Electroacupuncture Frequencies Functional disorder Future Generations Goals Heating Hindlimb Human Hyperalgesia Hypersensitivity Impairment Infusion procedures Insulin-Dependent Diabetes Mellitus Lead Lesion Mechanics Mediating Medical center Modeling Molecular National Center for Complementary and Alternative Medicine Needles Nerve Neural Pathways Neurons Neuropathy Neurotransmitters Nitrates Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Nitric Oxide Synthase Type I Nitrites Nociception Nucleus solitarius Opioid Opioid Receptor Pain Pain Threshold Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Play Postdoctoral Fellow Predisposition Principal Investigator Process Public Health Rattus Recovery Reflex action Regulation Reporting Research Personnel Role Science Sensory Sensory Process Signal Transduction Site Stimulus Streptozocin Structure Synaptic Transmission Syndrome System Techniques Temperature Testing Thalamic structure Therapeutic Effect Visceral Visceral pain Withdrawal afferent nerve base diabetic diabetic patient diabetic rat dorsal column experience foot gamma-Aminobutyric Acid immunoreactivity improved inhibitor/antagonist insight midbrain central gray substance neurochemistry novel novel strategies pressure public health relevance research study response sensory neuropathy somatosensory type I and type II diabetes vibration vibration perception

项目摘要

DESCRIPTION (provided by applicant): The most common forms of diabetic neuropathies are sensory dysfunctions with hyperalgesia and reduced temperature and vibration perception thresholds, which lead to very distressing and debilitating clinical complications. The gracile nucleus and nucleus tractus solitarius (NTS) were recently shown to modulate nociceptive and somatosensory reflexes. We found that the mechanical tolerance threshold and withdrawal latencies of heat and cold stimuli to the hind foot are consistently decreased in Zucker diabetic Fatty (ZDF) rats. Hyperalgesia and hypersensitivity to temperature/ pressure in ZDF rats are improved by low-frequency electroacupuncture (EA) stimulation of acupoint ST36. We have demonstrated that neuronal nitric oxide (NO) synthase (nNOS) expression is predominantly increased in the gracile nucleus and NTS following EA ST36 in rats. Our preliminary studies show that endogenous NO is decreased in the gracile nucleus in ZDF rats, and dialysate NO release in the nucleus is enhanced by EA ST36. The analgesic responses to EA ST36 are facilitated by L-arginine NO and blocked by an inhibitor of NO synthesis in the gracile nucleus. The results support the following hypotheses: 1) EA ST36 induces endogenous NO synthesis/release in the gracile nucleus and the NTS; and 2) NO-cGMP-GABA system in the dorsal medulla inhibits somatosensory/nociceptive susceptibility resulting in improvement of sensory neuropathies. In view of the critical importance of NO on sensory/nociceptive regulation, the major aims are: 1) Examine whether NO release in the gracile nucleus/NTS is increased and is positively correlated to anti-nociceptive/hypersensitive responses to low-frequency EA ST36; 2) Determine whether hyperalgesia and hypersensitivity to temperature/pressure in neuropathic rats are improved and are parallel to enhanced cFos-nNOS expressions in the gracile nucleus/NTS-thalamic pathways by 8 sessions of EA ST36; 3) Investigate whether anti-nociceptive/hypersensitive responses to EA ST36 are improved by administration of NO donors and worsened by an inhibitor of NO synthesis in the gracile nucleus and/or NTS in ZDF rats; and 4) Determine whether NO-cGMP-GABA cascade in the gracile nucleus and NTS responds to NO-mediated anti-nociceptive/hypersensitive responses to acupuncture in ZDF rats. Physiological recordings of pressure, temperature, and pain thresholds will be incorporated with neuropharmacological manipulations, chemical assays and EA/acupuncture to test the hypotheses in ZDF vs. lean rats. The results will advance our understanding of the mechanisms of EA/acupuncture- induced NO with cGMP-GABA cascade in the gracile nucleus/NTS on sensory/pain modulation, and yield new insights into effects of acupuncture on nNOS-NO generation in the dorsal medulla resulting in improvement of sensory diabetic neuropathies. PUBLIC HEALTH RELEVANCE: These studies should advance our understanding of the biochemical mechanisms of acupuncture-induced nitric oxide on sensory/pain regulation in the dorsal medulla, and reveal a therapeutic effect of acupuncture on improving hyperalgesia and hypersensitivity by affecting nitric oxide release/synthesis in the brain sites. The results should benefit public health by exploring a novel anti-nociceptive mechanism of acupuncture and by establishing a better acupuncture therapy based on scientific evidence of inducing nitric oxide and its synthase in the dorsal medulla for treatment of sensory diabetic neuropathies and other pain syndromes.

描述（由申请人提供）：糖尿病神经病的最常见形式是感官功能障碍，温度降低，温度和振动感知阈值降低，导致非常令人痛苦和衰弱的临床并发症。最近证明，格丝核和小核Tractus solitarius（NTS）调节伤害性和体感反射。我们发现，在扎克糖尿病脂肪（ZDF）大鼠中，对后脚的热和冷刺激的机械耐受性阈值和戒断潜伏期始终减少。 ZDF大鼠温度/压力的超敏反应和低频电针（EA）刺激兆头ST36可改善。我们已经证明，在大鼠的EA ST36之后，在gracile核和NTS中，神经元一氧化氮（NO）合酶（NNOS）表达主要增加。我们的初步研究表明，在ZDF大鼠的gracile核中内源性NO降低，而EA ST36增强了核中透析核的NO释放。 l-精氨酸NO促进对EA ST36的镇痛反应，并被格丝核中NO合成的抑制剂阻塞。结果支持以下假设：1）EA ST36诱导内源性NO合成/释放，在gracile核和NTS中； 2）背髓质中的无CGMP-GABA系统抑制体感/伤害感受敏感性，从而改善了感觉神经病。鉴于NO对感觉/伤害性调节的重要性至关重要，主要目的是：1）检查是否会增加Gracile Nucleus/nts中的NO释放，并且与对低频EA ST36的抗伤害感受/超敏的反应呈正相关； 2）确定神经性大鼠中温度/压力的高敏性和高敏性是否得到改善，并平行于GRACILE核/NTS-丘脑途径中的CFOS-NNOS表达增强，EA ST36的8个会话； 3）研究是否通过施用无供体来改善对EA ST36的抗伤害感/超敏反应，并因ZDF大鼠的gracile核和/或NTS中无合成的抑制剂而恶化。 4）确定gracile核中的NO-CGMP-GABA级联反应是否响应于ZDF大鼠对针灸的NO介导的抗伤害感受/过度敏感反应。压力，温度和疼痛阈值的生理记录将与神经药物操纵，化学测定和EA/针灸一起纳入ZDF与瘦大鼠中的假设。结果将提高我们对Gracile Nucleus/nts中CGMP-GABA级联反应的EA/针灸机制的理解，并在感觉/疼痛调节中对NNOS-NO对NNOS-NO的影响产生新的见解，从而在感觉型糖尿病神经疗法的改善中产生新的见解。公共卫生相关性：这些研究应提高我们对针灸诱导的一氧化氮对背髓质感觉/疼痛调节的生化机制的理解，并揭示针灸对改善痛苦和超敏性的治疗作用，并通过影响一氧化氮氧化释放/脑部合成。该结果应通过探索针灸的新型抗伤害感受机制，并基于基于诱导一氧化氮及其在背髓中诱导一氧化氮的科学证据来治疗感觉糖尿病神经病和其他疼痛综合症的科学证据来使公共卫生受益。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of electroacupuncture Zusanli (ST36) on food intake and expression of POMC and TRPV1 through afferents-medulla pathway in obese prone rats.

DOI：
10.1016/j.peptides.2012.10.009
发表时间：
2013-02
期刊：
Peptides
影响因子：
3
作者：
Ji B;Hu J;Ma S
通讯作者：
Ma S

Impaired expression of neuronal nitric oxide synthase in the gracile nucleus is involved in neuropathic changes in Zucker Diabetic Fatty rats with and without 2,5-hexanedione intoxication.

在有或没有 2,5-己二酮中毒的 Zucker 糖尿病肥胖大鼠中，薄核中神经元一氧化氮合酶的表达受损与神经病理性变化有关。

DOI：
10.1016/j.neures.2015.10.007
发表时间：
2016
期刊：
Neuroscience research
影响因子：
2.9
作者：
Ma,Sheng-Xing;Peterson,RichardG;Magee,EdwardM;Lee,Paul;Lee,Wai-NangPaul;Li,Xi-Yan
通讯作者：
Li,Xi-Yan

Infrared heat treatment reduces food intake and modifies expressions of TRPV3-POMC in the dorsal medulla of obesity prone rats.