Peripheral Sensitization Following Spinal Cord Injury

描述（由申请人提供）：脊髓损伤（SCI）导致运动和躯体感觉功能严重受损。躯体感觉的改变包括持续患者一生的中枢神经性疼痛（CNP）。CNP发生在大多数SCI患者中，对生活质量产生不利影响，导致自杀频繁发生。这是一个重大的，知之甚少的公共卫生问题，了解CNP的潜在机制应导致干预的机会，以防止这种可怕的情况。我们的总体目标是确定SCI后CNP的机制。我们使用啮齿动物脊髓挫伤模型，因为该模型最接近人类SCI。该模型中的CNP包括高于水平（前肢）、处于水平（躯干）和低于水平（后肢）的疼痛样行为，类似于在人类SCI中观察到的疼痛样行为。理论是脊髓机制引起CNP，由挫伤时细胞外谷氨酸增加产生。然而，我们的初步数据表明，机械和热致敏发生在肋间神经（水平）和前肢（水平以上）的初级传入伤害感受器中，后者是脊髓或外周神经没有损伤的位置。我们的假设是，一个混响循环是建立在损伤诱导的谷氨酸释放在脊髓开始。谷氨酸产生背根反射（DRR），导致外周神经源性炎症（从外周释放神经肽）。神经源性炎症导致初级传入纤维的外周敏化，初级传入纤维敏化背角神经元。一旦这种回响循环建立起来，就会长期维持下去。为了支持这一假设，我们的初步数据表明，与对照组相比，SCI大鼠颈传入神经中存在异常高的DRR活性。脊髓损伤后C和A5神经纤维自发DRR的放电率显著升高，A5神经纤维诱发DRR的百分比增加，鞘内注射荷包牡丹碱（GABAA拮抗剂）可使其减少。这些数据提供了脊髓（损伤部位）和外周传入神经之间的关键联系。我们的具体假设是，初级传入有助于CNP的中枢致敏，阻断DRR和/或外周致敏将减弱CNP。为了检验这一假设，目的1将确定SCI后外周和中枢致敏的时间过程;目的2将证明用谷氨酸拮抗剂治疗SCI大鼠可降低CNP，表现为疼痛行为减少、外周和中枢致敏减弱以及DRR降低。相反，鞘内谷氨酸盐给药未处理大鼠将产生CNP的这些体征。目的3将证明阻断DRR将减弱中枢和外周致敏和神经源性炎症。在这个建议中，我们将阐明机制，迄今为止一直是未知的贡献者中枢神经性疼痛。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) leads to severe impairments in locomotor and somatosensory function. Alterations in somatosensation include central neuropathic pain (CNP) which persists for the patient's life. CNP occurs in the majority of SCI patients, so adversely affecting the quality of life that suicide frequently ensues. This is a major, poorly understood, public health problem and understanding the mechanisms underlying CNP should lead to opportunities for intervention to prevent this terrible condition. Our overall goal is to identify mechanisms contributing to CNP following SCI. We use the rodent spinal cord contusion model since this model best approximates human SCI. CNP in this model includes above level (forelimb), at level (trunk) and below level (hindlimb) pain-like behaviors that resemble those seen in human SCI. The dogma is that spinal mechanisms give rise to CNP, generated by increased extracellular glutamate at the time of contusion. Our preliminary data, however, show that mechanical and thermal sensitization occurs in primary afferent nociceptors in the intercostal nerves (at level) and in the forelimbs (above level), the latter being a location where there is no damage to either the spinal cord or peripheral nerves. Our hypothesis is that a reverberating loop is set up beginning with injury-induced release of glutamate in the cord. The glutamate generates dorsal root reflexes (DRRs) that cause peripheral neurogenic inflammation (from release of neuropeptides peripherally). The neurogenic inflammation leads to peripheral sensitization of primary afferent fibers which sensitizes dorsal horn neurons. Once this reverberating loop is established, it is maintained chronically. In support of this hypothesis, our preliminary data demonstrate the presence of abnormally high DRR activity in cervical afferents in SCI rats compared to controls. The discharge rate of spontaneous DRRs in C and A5 fibers is significantly elevated in SCI cervical afferents, the percentage of A5 fibers with evoked DRRs is increased and these are reduced by intrathecal bicuculline, a GABAA antagonist. These data provide a critical link between the spinal cord (the site of injury) and the peripheral afferents. Our specific hypothesis is that primary afferents contribute to the central sensitization underlying CNP, and blocking DRRs and/or peripheral sensitization will attenuate CNP. To test this hypothesis, aim 1 will determine the time course of peripheral and central sensitization following SCI; aim 2 will demonstrate that treatment of SCI rats with glutamate antagonists reduces CNP, evidenced by reduced pain behaviors, attenuation of both peripheral and central sensitization and decreased DRRs. Conversely, treatment of naive rats with intrathecal glutamate will produce these signs of CNP. Aim 3 will demonstrate that blocking DRRs will attenuate central and peripheral sensitization and neurogenic inflammation. In this proposal we will elucidate mechanisms that heretofore have been unknown contributors to central neuropathic pain.