Long-term activation of spinal opioid analgesia after inflammation

炎症后脊髓阿片类药物镇痛的长期激活

• 批准号: 8840114
• 负责人: BRADLEY K. TAYLOR
• 金额: $ 61.02万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840114
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Adenylate Cyclase; Affect; Affective; Agonist; American; Analgesics; Behavior; Behavioral; Binding; Brain; Burn injury; Chronic; Cutaneous; Cyclic AMP; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease remission; Dynorphins; Electrophysiology (science); Enkephalins; Equilibrium; Event; Excitatory Postsynaptic Potentials; Failure; Feedback; Figs - dietary; Goals; Guanosine Triphosphate; Healed; Hernia; Homeostasis; Human; Hyperalgesia; Inflammation; Inguinal region; Injury; Knockout Mice; Knowledge; Lead; Masks; Mediating; Messenger RNA; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Naloxone; Naltrexone; Neurons; Nociception; Nociceptors; Operative Surgical Procedures; Opioid; Opioid Peptide; Opioid Receptor; Pain; Pain Nature; Pain management; Phase; Phosphorylation; Physical Function; Physiologic pulse; Posterior Horn Cells; Postoperative Pain; Presynaptic Terminals; Process; Productivity; Protein Isoforms; Proteins; Public Health; Publishing; Quality of life; Receptor Activation; Relapse; Resolution; Science; Secondary Hyperalgesias; Signal Transduction; Site; Slice; Spinal; Spinal Cord; Stress; Synapses; Synaptosomes; Syndrome; System; Testing; Tissues; Translating; Vision; Work; adenylyl cyclase 1; allostasis; central sensitization; chronic pain; cost; delta opioid receptor; dorsal horn; endogenous opioids; healing; heat injury; inhibitor/antagonist; innovation; mental function; mouse model; mu opioid receptors; naltrexol; neurobiological mechanism; pain behavior; patch clamp; peripheral pain; prevent; public health relevance; receptor; relating to nervous system; repaired; response; spinal nerve posterior root; spontaneous pain; trafficking

DESCRIPTION (provided by applicant): 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 b 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.

描述（由申请人提供）：严重的组织损伤会产生中心敏化（CNS伤害性神经元对正常或亚阈值传入输入的反应性），这会导致Hypergesia。潜在的敏化（LS）是一种无声的中央敏化形式，在组织愈合后持续存在，明显的痛觉过敏迹象已经解决。 LS可以用“重新点燃”或恢复痛觉过敏的阿片受体拮抗剂或反激动剂揭示。因此，LS期间的疼痛缓解可能是通过掩盖LS的引起感受性成分的补品阿片受体活性来维持的。 LS很重要，因为它会刺激伤害性系统，因此，当抑制系统失败时，会发生痛苦发作。理解LS的关键第一步是证明翻译意义，我们现在表明，阿片受体反向激动剂Naloxone可以恢复实验性疼痛后在一级热损伤后进行继发性超级过敏后1周递送1周。具体目的1检验了燃烧或手术会触发人类中LS和长期阿片类镇痛的假设。为了进一步研究LS的神经生物学机制，我们还将使用长期持久，强大，广泛范围，可重复并转化为人类研究的小鼠模型。我们发现，即使在组织损伤几个月后给药，MU阿片受体（MOR）逆动力学家恢复了痛觉过敏的行为和分子迹象，这需要NMDA受体受体的激活1（AC1）。我们的结果很重要，因为它们表明在LS期间会干扰MOR镇痛的任何事件，都会导致人类慢性疼痛综合征中的痛觉过敏复发。具体目的2检验了MOR的本构活性（MORCA）和/或MOR，DELTA（DOR）的激活或通过阿片类肽在DH或Rostroventromedial延髓中维持内源性镇痛，从而将LS限制在疼痛缓解状态的情况下。具体目标3确定了MOR在DH（使用创新的64通道田间记录系统）中抑制空间协调的神经活性的程度和在LS期间在LS期间的原代传入伤害感受器或DH神经元的突触前末端的突触强度的程度。然后，特定的目标4然后测试MOR是否特异性抑制脊柱NMDA受体亚基（Glun2a或Glun2b）和/或EPAC1（最近被CAMP直接激活的交换蛋白，最近发现有助于周围疼痛剂量）以阻止LS期间的疼痛。该项目的完成将使我们更接近减轻慢性疼痛B的长期目标：a）促进内源性阿片类镇痛，从而限制了LS在缓解状态下；或b）完全熄灭LS，例如使用选择性AC1或EPAC1抑制剂。我们的一般模型和假设与Allostasis的概念具有相似之处：相反的过程（MOR和LS）之间通过相互反馈相互促进的病理学平衡。我们的长期视野是慢性疼痛疗法，恢复体内平衡的一种新的概念策略，在那里既没有中央敏感性也没有道理的补偿性反应。