Morphine undermines recovery of function after SCI: Neurobiological mechanisms

描述(申请人提供)：吗啡是最常用的止痛药之一，用于治疗脊髓损伤(SCI)后的神经性疼痛。尽管吗啡被广泛使用，但在脊髓损伤模型中，关于吗啡给药的次要后果的研究很少。不幸的是，我们的研究表明，脊髓损伤后急性给予吗啡有继发性影响，减少运动功能的恢复，加剧神经病理性疼痛症状，并在挫伤的慢性期增加损伤面积。这些数据强调了进一步研究阿片类药物在脊髓损伤模型中影响的必要性。为了解决这个问题，我们将调查脊髓挫伤后注射吗啡的分子后果。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(与鞘内吗啡联合给药)来研究脊髓突起的作用。在其他模型中，有三个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，以及c)胶质细胞上的非经典阿片受体。这些实验旨在直接研究这些受体系统在脊髓损伤后吗啡诱导的功能减退中的作用，以及神经回路的“过度兴奋”所起的作用。我们的工作假设是，吗啡通过激活神经元上经典的m-阿片受体产生抗伤害性(疼痛抑制)。然而，在受损的脊髓部位，k-阿片和神经胶质非经典阿片受体的激活可能会增强炎症反应和过度兴奋，这是脊髓损伤急性期固有的，并破坏神经系统的可塑性，增加细胞死亡。其次，我们的目标是调节脊髓分子的变化，保护功能恢复，同时使用临床相关的全身吗啡给药途径来产生止痛。我们假设我们可以用k-阿片受体拮抗剂或米诺环素在脊髓水平阻断吗啡的作用，或用米诺环素来阻断非经典阿片类神经胶质细胞的激活。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/或非经典阿片受体而产生的变化。为了这第三个目标，我们计划以特定的受体系统为目标，并使用聚类分析来确定哪些分子终点与吗啡给药的特定后果存在协同变化。这一建议创新性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上阻断阿片类药物不良影响的药理学干预措施，同时增加吗啡在脊髓损伤后的有益(抗伤害)作用。 公共卫生相关性：吗啡破坏脊髓损伤后功能的恢复：衍生分子机制项目叙事吗啡是治疗脊髓损伤后神经病理性疼痛(SCI)最有效和最常用的处方镇痛剂之一。然而，不幸的是，最近的研究表明，吗啡可能在脊髓损伤后产生不良的继发性影响，延缓运动功能的恢复，增加组织丢失，并在损伤的慢性阶段产生反常疼痛的症状。为了提高脊髓损伤后使用阿片类药物的安全性和止痛效果，拟议的实验将1)确定吗啡作用下的关键分子变化，2)在脊髓水平使用药物操作来阻断不良反应(减少恢复，组织丢失)，并增强吗啡的有益(止痛)作用，3)进一步了解神经病理性疼痛的致病分子机制。

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. PUBLIC HEALTH RELEVANCE: Morphine undermines recovery of function after SCI: Deriving molecular mechanisms Project Narrative Morphine is one of the most effective and most commonly prescribed analgesics for the treatment of neuropathic pain after a spinal cord injury (SCI). Unfortunately, however, recent research suggests that morphine may have adverse secondary effects after SCI, attenuating the recovery of locomotor function, increasing tissue loss, and producing symptoms of paradoxical pain in the chronic stages of injury. To improve the safety and analgesic efficacy of opioids used after SCI, the proposed experiments will 1) identify critical molecular changes that underlie morphine's effects, 2) use pharmacological manipulations to block adverse effects (reduced recovery, tissue loss) at a spinal level, and potentiate morphine's beneficial (analgesic) effects, and 3) further understanding of the causal molecular mechanisms in neuropathic pain.