Morphine undermines recovery of function after SCI: Neurobiological mechanisms

吗啡会破坏 SCI 后功能的恢复：神经生物学机制

• 批准号: 8426179
• 负责人: MICHELLE A HOOK
• 金额: $ 26.37万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426179
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Affect; Agonist; Analgesics; Animal Model; Apoptosis; Area; Attenuated; Behavioral; Cell Death; Cellular Assay; Chemosensitization; Chronic; Chronic Phase; Clinical; Cluster Analysis; Contusions; Couples; Data; Dose; Dynorphins; Heat-Shock Proteins 90; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intractable Pain; Lesion; Limb structure; Link; Locomotor Recovery; Mediating; Minocycline; Modeling; Molecular; Molecular Models; Molecular Target; Morphine; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Narcotic Antagonists; Neuroglia; Neuronal Plasticity; Neurons; Opioid; Opioid Receptor; Outcome; Pain; Pain management; Paralysed; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Population; Process; Receptor Activation; Recovery; Recovery of Function; Research; Rodent; Role; Route; Safety; Site; Spinal; Spinal Anesthesia; Spinal Injuries; Spinal cord injury; Staging; Symptoms; System; TLR2 gene; Testing; Tissues; Work; attenuation; base; chronic pain; clinically relevant; cytokine; endogenous opioids; improved; inhibitor/antagonist; innovation; molecular modeling; neglect; neural circuit; neurobiological mechanism; neuropathology; neurotoxicity; pain inhibition; painful neuropathy; prevent; public health relevance; receptor; receptor function; research study; response; therapy development; toll-like receptor 4

DESCRIPTION (provided by applicant): Morphine is one of the most frequently prescribed analgesics for the treatment of neuropathic pain after a spinal cord injury (SCI). Despite widespread use, there has been very little research on the secondary consequences of morphine administration in a spinal injury model. Unfortunately, our research suggests that the acute administration of morphine after SCI has secondary effects that reduce recovery of locomotor function, exacerbate neuropathic pain symptoms, and increase lesion size in the chronic phase of a contusion injury. These data underscore the need for further research on the effects of opioids in a SCI model. To address this issue, we will investigate the molecular consequences of morphine administration after a spinal contusion injury. Three aims are proposed. First, we will examine the role of spinal processes using agonists and antagonists (co-administered with intrathecal morphine) for classic and non-classic opioid receptors. In other models, three receptor systems have been implicated in the direct effects of morphine, including a) the m- opioid receptor, b) the k-opioid receptor, and c) non-classic opioid receptors on glia. The experiments proposed here aim to directly investigate the contribution of these receptor systems, and the role of 'overexcitation' of neural circuitry, in the morphine-induced attenuation of function after SCI. Our working hypothesis is that morphine produces antinociception (pain inhibition) through activation of classic m-opioid receptors on neurons. At compromised spinal loci, however, activation of k-opioid and glial non-classic opioid receptors may potentiate inflammatory responses and overexcitation, intrinsic to the acute phase of spinal injury, and undermine the plasticity of the neural system as well as increase cell death. Secondly, we aim to modulate spinal molecular changes, to protect functional recovery, while using a clinically relevant systemic route of morphine administration to produce analgesia. We hypothesize that we can block the effects of morphine at the spinal level using k-opioid receptor antagonists, or minocycline to block non-classic opioid activation of glia. We will also test the effects of overexcitation by blocking spinal NMDA receptor function with MK-801. Finally, we will identify cellular changes inherent to the contusion injury itself, and those produced though activation of classic and/or non-classic opioid receptors. For this third aim, we plan to target specific receptor systems, and use a cluster analysis to ascertain which molecular end-points co-vary with specific consequences of morphine administration. This proposal innovatively couples modern discoveries in opioid pharmacology with research on spinal cord injury. Most importantly, it will allow us to identify pharmacological interventions that block the adverse effects of opioids at a spinal level, while increasing morphine's beneficial (antinociceptive) effects after SCI.

描述（由申请人提供）：吗啡是治疗脊髓损伤（SCI）后神经性疼痛的最常用处方镇痛药之一。尽管广泛使用，但在脊髓损伤模型中对吗啡给药的继发性后果的研究很少。不幸的是，我们的研究表明，脊髓损伤后急性吗啡给药具有继发性影响，减少运动功能的恢复，加重神经性疼痛症状，并增加挫伤慢性期的病变大小。这些数据强调需要进一步研究阿片类药物在SCI模型中的作用。为了解决这个问题，我们将研究脊髓挫伤后吗啡给药的分子后果。提出了三个目标。首先，我们将使用经典和非经典阿片受体的激动剂和拮抗剂（与鞘内吗啡共同给药）研究脊髓过程的作用。在其他模型中，三种受体系统与吗啡的直接作用有关，包括a）m-阿片受体，B）k-阿片受体，和c）神经胶质上的非经典阿片受体。这里提出的实验旨在直接调查这些受体系统的贡献，以及“过度兴奋”的神经回路的作用，在脊髓损伤后吗啡诱导的功能衰减。我们的工作假设是，吗啡通过激活神经元上的经典m-阿片受体产生抗伤害感受（疼痛抑制）。然而，在受损的脊髓位点，k-阿片样物质和神经胶质非经典阿片样物质受体的激活可能会增强脊髓损伤急性期固有的炎症反应和过度兴奋，破坏神经系统的可塑性以及增加细胞死亡。其次，我们的目标是调节脊髓分子的变化，以保护功能恢复，同时使用临床相关的全身吗啡给药途径产生镇痛。我们假设，我们可以在脊髓水平使用K-阿片受体拮抗剂阻断吗啡的作用，或米诺环素阻断神经胶质细胞的非经典阿片激活。我们还将通过用MK-801阻断脊髓NMDA受体功能来测试过度兴奋的影响。最后，我们将确定挫伤本身固有的细胞变化，以及通过激活经典和/或非经典阿片受体产生的细胞变化。对于这第三个目标，我们计划针对特定的受体系统，并使用聚类分析，以确定哪些分子终点与吗啡给药的特定后果共变。这项提案创新地将阿片类药物药理学的现代发现与脊髓损伤的研究结合起来。最重要的是，它将使我们能够确定在脊髓水平阻断阿片类药物的不良作用的药理学干预，同时增加SCI后吗啡的有益（抗伤害）作用。