Peripheral Sensitization Following Spinal Cord Injury

描述（由申请人提供）：脊髓损伤（SCI）导致运动和体感觉功能严重受损。躯体感觉的改变包括中枢神经性疼痛（CNP），这种疼痛会伴随患者一生。CNP发生在大多数SCI患者中，因此对生活质量产生不利影响，导致自杀频繁发生。这是一个主要的，知之甚少的公共卫生问题，了解CNP的潜在机制应该会带来干预的机会，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，因为这个模型最接近人类脊髓损伤。该模型中的CNP包括水平以上（前肢），水平以下（躯干）和水平以下（后肢）的疼痛样行为，类似于人类SCI中所见的行为。教条是脊髓机制引起CNP，由挫伤时细胞外谷氨酸增加产生。然而，我们的初步数据显示，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，后者是脊髓或周围神经没有损伤的位置。我们的假设是，从损伤引起的脊髓谷氨酸释放开始，一个回响循环就建立起来了。谷氨酸产生背根反射（DRRs），引起周围神经源性炎症（来自周围神经肽的释放）。神经源性炎症导致初级传入纤维外周敏化，使背角神经元敏化。一旦建立了这个混响回路，它就会长期维持下去。为了支持这一假设，我们的初步数据表明，与对照组相比，脊髓损伤大鼠的颈椎事件中存在异常高的DRR活动。脊髓损伤后，C和A5纤维自发性DRRs放电率显著升高，A5纤维诱发DRRs的比例增加，而鞘内双管碱（GABAA拮抗剂）可降低这些比例。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，原发性事件有助于CNP的中枢敏化，阻断DRRs和/或外周敏化将减弱CNP。为了验证这一假设，目的1将确定脊髓损伤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脊髓损伤大鼠可以减少CNP，这可以通过疼痛行为的减少、外周和中枢敏化的减弱以及DRRs的降低来证明。相反，用鞘内谷氨酸治疗幼稚大鼠会产生这些CNP的迹象。目的3将证明阻断DRRs将减轻中枢和外周致敏和神经源性炎症。在本提案中，我们将阐明迄今为止未知的中枢神经性疼痛的机制。

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.