Injury-Induced Pain: Chemical Modulation of Nociceptors

损伤引起的疼痛：伤害感受器的化学调节

基本信息

批准号：
10063909
负责人：
SRINIVASA N. RAJA
金额：
$ 35.82万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063909
关键词：
Acute Adult Adverse effects Affect Affective Afferent Neurons Agonist Animal Model Animals Anti-Inflammatory Agents Attenuated Behavior Behavioral Assay Biological Biological Assay CNR1 gene Calcium Cannabinoids Capsaicin Chemical Stimulation Chemicals Chronic Clinical Constipation Cyclic AMP Development Dose Economic Burden Enzyme-Linked Immunosorbent Assay Fluorescence Ganglia Grant Hypersensitivity Image Immune Impaired cognition Impairment In Vitro Individual Injury Knockout Mice Ligation Mechanics Mediating Mus Neuraxis Neurons Nociception Nociceptors Opioid Outcome Measure Pain Pain management Patients Penetration Peripheral Peripheral Nervous System Persistent pain Pharmaceutical Preparations Population Posterior Horn Cells Principal Investigator Public Health Raja Reflex action Reporting Research Rodent Model Role Running Sedation procedure Serum Site Slice Societies Spinal Spinal Cord Spinal nerve structure Subgroup Symptoms Synaptic Transmission TRPV1 gene Tactile Testing Therapeutic Tissues Translations Western Blotting addiction attenuation base behavior test beta-Alanine cannabinoid receptor cell motility chronic constriction injury chronic pain conditional knockout conditioned place preference cytokine dorsal horn drug action extracellular global health immune function in vivo in vivo calcium imaging innovation insight interdisciplinary approach mu opioid receptors nerve injury neurophysiology novel pain inhibition pain relief painful neuropathy patch clamp peripheral pain pre-clinical programs receptor recombinase-mediated cassette exchange response side effect societal costs spontaneous pain transmission process treatment strategy tyrosyl-arginyl-phenylalanyl-lysinamide voltage

项目摘要

PROJECT SUMMARY The treatment of neuropathic pain (NP) remains unsatisfactory and presents a major global health and economic burden to individuals and society. Unfortunately, currently available medications are not uniformly effective and are associated with significant central nervous system (CNS) side effects that limit their clinical utility. Translation from preclinical findings to a viable clinical therapy for NP has been fraught with disappointments, possibly because animal studies have primarily relied on outcome measures such as reflex responses that fail to mimic the chief symptom of spontaneous and ongoing pain in patients. Our recent studies suggested that peripherally acting µ-opioid receptor (MO-R) agonists alleviate mechanical and heat hypersensitivities in rodent models of NP. Here, our preliminary studies also indicate a role for peripheral cannabinoid receptors (CB-R) in NP, and further suggest that both peripheral MO-R and CB-R are valuable targets for alleviating ongoing pain after nerve injury. Based on these novel findings, we hypothesize that: 1) Activation of CB1-R and MO-R in the peripheral nervous system (PNS) attenuates ongoing NP, and has no significant adverse effects that would suggest CNS penetration, impaired G.I. motility, or undesirable immune effects; 2) Subpopulations of DRG neurons, especially those that express CB1-R, MO-R, and TRPV1, develop spontaneous activity after injury that can be inhibited by peripherally acting CB1-R and MO-R agonists; 3) Activation of peripheral neuronal CB1-R and MO-R decreases nociceptive transmission in dorsal horn neurons; 4) CB1-R agonists enhance peripherally acting MO-R agonist-induced inhibition of NP-related behavior by potentiating MO-R-mediated inhibition of DRG neurons. A broad range of strategies will be used to rigorously test our hypotheses in three inter-related Aims. In Aim 1, the efficacy, receptor subtypes involved, and potential adverse effects of systemic administration of the drugs will be studied. In Aim 2, we will use calcium imaging, patch clamp recording in spinal cord slices, and in vivo dorsal horn recordings to determine the mechanisms by which CB13 and DALDA inhibit ongoing NP in the PNS. In Aim 3, we will examine the functional interactions between CB1-R and MO-R in PNS for NP inhibition. Our study involves comprehensive and innovative approaches including: Operant behavioral tests to reveal the relief of ongoing and affective components of NP, high-throughput Pirt-GCaMP6 calcium imaging of DRG neurons in vivo, peripherally restricted CB1-R and MO- R conditional knockout (cKO) mice using a Cre/loxP system, neurophysiologic recordings in functionally distinct subgroups of dorsal horn neurons (e.g., excitatory, GABAergic inhibitory) identified by fluorescence, and multiplex cytokine ELISA. The results of these studies will provide new insights into the mechanisms that underlie the peripheral pain-inhibitory effects of opioids and cannabinoids, and will contribute to the development of novel, translatable therapeutic strategies for the treatment of NP that may be associated with minimal adverse effects. Accordingly, the scientific premise, innovation, and rigor of our proposal are high.

项目摘要神经性疼痛（NP）的治疗仍然不令人满意，并且具有主要的全球健康状况经济焚烧个人和社会。不幸的是，目前可用的药物并不统一有效，并且与限制其临床的重要中枢神经系统（CNS）有关公用事业。从临床前发现转换为NP的可行临床疗法的翻译已被造成失望，可能是因为动物研究主要取决于结果指标，例如反射无法模仿患者发起和持续疼痛的主要症状的反应。我们的最新消息研究表明，外周作用µ-阿片受体（MO-R）激动剂减轻了机械和热量 NP啮齿动物模型中的超源性。在这里，我们的初步研究也表明了外围的作用 NP中的大麻素受体（CB-R），进一步表明外围MO-R和CB-R都有价值减轻神经损伤后持续疼痛的靶标。基于这些新颖的发现，我们假设：1）周围神经系统（PNS）中CB1-R和MO-R的激活减弱了持续的NP，没有 G.I.运动性或不良免疫效果； 2）DRG神经元的亚群，尤其是表达CB1-R，MO-R和TRPV1的亚群受伤后的赞助活动可以被周围作用的CB1-R和MO-R激动剂抑制； 3）周围神经元CB1-R和MO-R的激活可降低背角神经元中的伤害感受器。 4）CB1-R激动剂增强了外围作用MO-R激动剂诱导的NP相关行为的抑制增强MO-R介导的DRG神经元的抑制作用。广泛的策略将用于严格在三个相互关联的目标中测试我们的假设。在AIM 1中，涉及效率，受体亚型和潜力全身给药药物的不利影响将研究。在AIM 2中，我们将使用钙成像，脊髓切片中的斑块夹记录和体内背角记录，以确定机制 CB13和DALDA抑制PNS中持续的NP。在AIM 3中，我们将检查功能相互作用在PNS中的CB1-R和MO-R之间进行NP抑制。我们的研究涉及全面和创新方法包括：操作行为测试，以揭示NP的持续和情感成分的缓解， DRG神经元在体内，外周受限的CB1-R和MO-的高通量PIRT-GCAMP6钙成像 R条件敲除（CKO）小鼠使用CRE/LOXP系统，功能中的神经生理记录通过荧光鉴定的背角神经元（例如兴奋性，GABA能抑制）的不同亚组和多重细胞因子ELISA。这些研究的结果将为您提供有关机制的新见解阿片类药物和大麻素的周围抑制作用的基础是，将有助于开发新颖的可翻译理论策略，用于治疗NP 最小的不良反应。彼此之间，我们提议的科学信念，创新和严格性很高。

项目成果

期刊论文数量（100）

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 Combined Electrical Stimulation of the Dorsal Column and Dorsal Roots on Wide-Dynamic-Range Neuronal Activity in Nerve-Injured Rats.

背柱和背根联合电刺激对神经损伤大鼠宽动态范围神经元活动的影响。

DOI：
10.1111/ner.12341
发表时间：
2015
期刊：
Neuromodulation : journal of the International Neuromodulation Society
影响因子：
0
作者：
Yang,Fei;Zhang,Tong;Tiwari,Vinod;Shu,Bin;Zhang,Chen;Wang,Yun;Vera-Portocarrero,LouisP;Raja,SrinivasaN;Guan,Yun
通讯作者：
Guan,Yun

The global burden of neuropathic pain: IASP's educational and advocacy efforts to enhance the management of neuropathic pain sufferers.

神经性疼痛的全球负担：IASP 为加强对神经性疼痛患者的管理而开展的教育和宣传工作。