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Long-term activation of spinal opioid analgesia after imflammation - Supplement

炎症后脊髓阿片类药物镇痛的长期激活 - 补充

基本信息

批准号：
9816476
负责人：
BRADLEY K. TAYLOR
金额：
$ 39.23万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816476
关键词：
Absence of pain sensation Adenylate Cyclase Affect Agonist American Analgesics Behavioral Cyclic AMP Disease remission Electrophysiology (science)Equilibrium Event Feedback Goals Homeostasis Human Hyperalgesia Injury Masks Modeling Molecular N-Methyl-D-Aspartate Receptors Naloxone Neurons Nociception Nociceptors Operative Surgical Procedures Opioid Analgesics Opioid Antagonist Opioid Peptide Opioid Receptor Pain Pain management Pathologic Pharmaceutical Preparations Physical Function Presynaptic Terminals Process Productivity Proteins Public Health Quality of life Receptor Activation Relapse Resolution Secondary Hyperalgesias Spinal Stress Synapses Syndrome System Testing Tissues Translating Vision allostasis central sensitization chronic pain cost endogenous opioids healing heat injury inhibitor/antagonist innovation mental function mouse model mu opioid receptors neurobiological mechanism patch clamp peripheral pain public health relevance relating to nervous system response

项目摘要

Severe tissue injury generates central sensitization (increased responsiveness of CNS nociceptive neurons to normal or sub-threshold afferent input) that contributes to hyperalgesia. Latent sensitization (LS) is a silent form of central sensitization that persists after tissue has healed and overt signs of hyperalgesia have resolved. LS can be revealed with opioid receptor antagonists or inverse agonists that “rekindle” or reinstate hyperalgesia. Thus, pain remission during LS is likely maintained by tonic opioid receptor activity that masks the pronociceptive components of LS. LS is important because it primes nociceptive systems such that, when inhibitory systems fail, a pain episode ensues. A key first step in understanding LS is to demonstrate the translational significance, and we now show that the opioid receptor inverse agonist, naloxone, can reinstate experimental pain when delivered 1 wk after the resolution of secondary hyperalgesia following first degree thermal injury. Specific Aim 1 tests the hypothesis that burn or surgery triggers LS and long-term opioid analgesia in humans. To further study the neurobiological mechanisms of LS, we will also use a mouse model that is long-lasting, powerful, broad range, repeatable, and translates to human studies. We found that mu opioid receptor (MOR) inverse agonists reinstated behavioral and molecular signs of hyperalgesia, even when administered months after tissue injury, and this required NMDA receptor activation of adenylyl cyclase type 1 (AC1). Our results are important because they suggest that any event, such as stress, that interferes with MOR analgesia during LS will lead to relapse of hyperalgesia in chronic pain syndromes in humans. Specific Aim 2 tests the hypothesis that MOR constitutive activity (MORCA) and/or activation of MOR, delta (DOR), or kappa (KOR) receptors by opioid peptides in the DH or rostroventromedial medulla maintains endogenous analgesia and thereby restricts LS to a state of pain remission. Specific Aim 3 determines the extent to which MORs inhibit spatially coordinated neural activity in the DH (using an innovative 64-channel field recording system) and synaptic strength in presynaptic terminals of primary afferent nociceptors or on DH neurons (using patch clamp electrophysiology) during LS. Specific Aim 4 then tests whether MORs specifically inhibit spinal NMDA receptor subunits (GluN2A or GluN2B) and/or Epac1 (exchange protein directly activated by cAMP, recently found to contribute to peripheral pain senstization) to block pain during LS. Completion of this project will bring us closer to our long-term goal of alleviating chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether, for example with a selective AC1 or Epac1 inhibitor. Our general model and hypothesis shares similarities with the concept of allostasis: a pathologically-elevated balance between opposing processes (MOR and LS) that facilitate each other by mutual feedback. Our long-term vision is a new conceptual strategy for chronic pain therapy, to restore homeostasis, where there is neither central sensitization nor MOR compensatory responses.

严重的组织损伤产生中枢致敏（CNS伤害感受神经元对正常或阈下传入输入），其有助于痛觉过敏。潜伏致敏（Latent sensitization，LS）是一种无声的一种在组织愈合和明显的痛觉过敏症状消失后仍持续存在的中枢致敏形式。 LS可以用阿片受体拮抗剂或反向激动剂来显示，痛觉过敏因此，LS期间的疼痛缓解可能是通过抑制阿片受体活性来维持的， LS的原伤害感受成分。LS是重要的，因为它启动伤害感受系统，使得当抑制系统失效，疼痛发作。理解LS的关键第一步是证明翻译的意义，我们现在表明，阿片受体反向激动剂，纳洛酮，可以恢复，实验性疼痛时，交付后1周的决议继发性痛觉过敏后，第一度热损伤具体目标1检验烧伤或手术触发LS和长期阿片类药物的假设人类的镇痛为了进一步研究LS的神经生物学机制，我们还将使用小鼠模型这是持久的，强大的，广泛的，可重复的，并转化为人类研究。我们发现，阿片受体（莫尔）反向激动剂恢复痛觉过敏的行为和分子迹象，即使当在组织损伤后数月给药，这需要腺苷酸环化酶1型的NMDA受体激活（AC1）。我们的研究结果很重要，因为它们表明，任何干扰莫尔反应的事件，如压力， LS期间的镇痛将导致人类慢性疼痛综合征中痛觉过敏的复发。具体目标2 检验了莫尔组成型活性（MORCA）和/或莫尔、δ（DOR）或κ的激活 (KOR)DH或延髓头腹内侧区阿片肽受体维持内源性镇痛从而将LS限制在疼痛缓解的状态。具体目标3决定了MORs 抑制DH的空间协调神经活动（使用创新的64通道现场记录系统）和初级传入伤害感受器的突触前末梢或DH神经元上的突触强度（使用贴片钳位电生理学）。特异性目的4然后测试MORs是否特异性抑制脊髓NMDA 受体亚单位（GluN 2A或GluN 2B）和/或Epac 1（由cAMP直接激活的交换蛋白，最近发现有助于外周疼痛敏感化）以在LS期间阻断疼痛。该项目的完成将带来我们通过以下任一方式更接近我们缓解慢性疼痛的长期目标：a）促进内源性阿片样物质镇痛，从而将LS限制在缓解状态内;或者B）例如用选择性的 AC 1或Epac 1抑制剂。我们的一般模型和假设与变稳态的概念相似：相反过程（莫尔和LS）之间的病理性升高平衡，通过以下方式相互促进相互反馈我们的长期愿景是为慢性疼痛治疗提供一种新的概念策略，稳态，其中既没有中枢致敏也没有莫尔代偿反应。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair: study protocol for a randomized controlled trial.

DOI：
10.1186/s13063-015-1021-6
发表时间：
2015-11-10
期刊：
Trials
影响因子：
2.5
作者：
Pereira MP;Werner MU;Dahl JB
通讯作者：
Dahl JB

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

DOI：
10.1371/journal.pone.0242169
发表时间：
2020
期刊：
PloS one
影响因子：
3.7
作者：
Springborg AD;Jensen EK;Kreilgaard M;Petersen MA;Papathanasiou T;Lund TM;Taylor BK;Werner MU
通讯作者：
Werner MU

Demarcation of secondary hyperalgesia zones: Punctate stimulation pressure matters.

继发性痛觉过敏区的划分：点状刺激压力很重要。