Sensory Plasticity During Central Neuropathic Pain Caused by Spinal Cord Injury

脊髓损伤引起的中枢神经病理性疼痛的感觉可塑性

• 批准号: 7765622
• 负责人: EDGAR T. WALTERS
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765622
• 关键词: Action Potentials; Afferent Neurons; Animals; Antisense Oligonucleotides; Attention; Automobile Driving; Axon; Behavior; Behavioral; Binding; CD2 gene; Caliber; Capsaicin; Cells; Chronic; Clinical Treatment; Complex; Contusions; Data; Development; Dorsal; Excision; Filament; Ganglia; Generations; Growth; Hyperalgesia; In Vitro; Incidence; Injury; Intervention; Investigation; Link; Maintenance; Membrane; Membrane Potentials; Methods; Modeling; Motor; Myxoid cyst; Neurons; Nociception; Nociceptors; Pain; Pathway interactions; Patients; Peripheral; Pilot Projects; Play; Posterior Horn Cells; Preparation; Presynaptic Terminals; Process; Property; Protocols documentation; Rattus; Recovery; Reporting; Research; Resistance; Rest; Rhizotomy procedure; Role; Sampling; Sensory; Signal Transduction; Site; Sodium Channel; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Testing; Thoracic spinal cord structure; Time; Tissues; allodynia; base; behavior test; central pain; chronic pain; dorsal horn; extracellular; in vitro activity; in vitro testing; in vivo; knock-down; neuronal cell body; novel; painful neuropathy; prevent; public health relevance; selective expression; sham surgery; spinal cord injury pain; spinal nerve posterior root; spinal shock; spontaneous pain; voltage

Description (provided by applicant): Summary Persistent neuropathic pain is produced by spinal cord injury (SCI) in a majority of patients. Like other forms of central neuropathic pain, SCI pain is often debilitating and quite resistant to clinical treatment. Most research on mechanisms of SCI pain has focused on increases in the responsiveness and spontaneous electrical activity of central neurons within pain pathways, especially second-order neurons in the dorsal horn near the injury site. Hyperexcitability of dorsal horn neurons after SCI appears to involve many plausible causes, but one that has received little attention is an enhancement of spontaneous activity (SA) and excitability in the sensory neurons (especially nociceptors) that normally excite dorsal horn neurons. Indeed, surprisingly little is known about how sensory neurons in the dorsal root ganglion (DRG) respond to SCI. The proposed studies are based on the novel hypothesis that SCI triggers a chronic hyperfunctional state in nociceptors which results in the generation of SA within their somata in DRGs, and that this continuing SA excites central pain pathways, driving spontaneous pain, allodynia, and hyperalgesia. This hypothesis will be tested by 1) examining the effects of SCI on SA and electrophysiological properties of DRG neurons that are subsequently dissociated and tested in depth, 2) examining SA in DRG neurons in vivo after SCI, and 3) by attempting to block SA (and associated SCI pain) by disconnecting the DRG from the spinal cord (dorsal rhizotomy prior to the contusion) or by knocking down a voltage-gated Na+ channel that is necessary for the generation of SA by nociceptors. SCI will be produced in a standard contusion injury model, with the impact at spinal level T10. Behavioral and electrophysiological tests will be conducted 3 days, 1 month, and 3 months after injury. The behavioral tests will assess motor loss and possible recovery, and (at 1 and 3 months) spontaneous pain, allodynia, and hyperalgesia at, above, and below the injury level. In vitro electrophysiological tests will be conducted with whole-cell current clamp methods on DRG neurons dissociated from T9, T11, and L4 levels. In addition to recording SA, a complex test protocol will define intrinsic passive and active membrane properties at resting membrane potential and at holding potentials of -80 mV (where little inactivation of voltage-gated sodium channels occurs) and -50 mV (where many of these channels are inactivated). In vivo electrophysiological tests will use extracellular recording from filaments teased from the dorsal root to see how much SA is present before and after disconnecting the DRG from the periphery. Four predictions of the hyperfunctional nociceptor hypothesis will be tested: first, SCI should enhance SA of putative nociceptive DRG neurons, initially at and below the level of injury, but later above the injury as well. Second, that enhanced SA in vitro and in vivo, and hyperexcitability in vitro, should be correlated with enhanced behavioral signs of pain, allodynia, and hyperalgesia. Third, if SCI pain depends in part upon SA in nociceptors, SCI pain should be reduced by selectively suppressing nociceptor SA in vivo. This will be tested by delivering antisense oligonucleotides intrathecally to knock down the expression of a Na+ channel, Nav1.8, that is expressed selectively in nociceptive sensory neurons and is necessary for generating SA in these neurons. Fourth, the assumption that retrograde signals to nociceptor somata from central processes of these neurons are necessary for triggering the SA will be tested by performing a dorsal rhizotomy immediately before the SCI. These exploratory studies will test a novel hypothesis about mechanisms important for SCI pain, define intrinsic electrophysiological alterations in DRG neurons linked to neuropathic pain, and begin to test an intervention that appears potentially useful for treating SCI pain. PUBLIC HEALTH RELEVANCE: Spinal cord injury patients often suffer debilitating pain that is highly resistant to clinical treatments. Although most investigations of this problem have focused on alterations in central neurons within pain pathways, preliminary data suggest that alterations of sensory neurons that normally convey pain information from peripheral tissues may play an important role. The proposed studies will test the hypothesis that chronic pain caused by spinal cord injury is produced in part by spontaneous electrical activity in sensory neurons, and that pain may be reduced by blocking this activity.

描述（由申请人提供）：概述在大多数患者中，持续性神经性疼痛由脊髓损伤（SCI）引起。像其他形式的中枢神经性疼痛一样，脊髓损伤疼痛常常使人衰弱，并且对临床治疗相当有抵抗力。大多数关于脊髓损伤疼痛机制的研究都集中在疼痛通路中中枢神经元的反应性和自发电活动的增加，特别是损伤部位附近背角的二级神经元。脊髓损伤后背角神经元的高兴奋性似乎涉及许多合理的原因，但很少受到关注的一个原因是通常兴奋背角神经元的感觉神经元（特别是伤害感受器）的自发活动（SA）和兴奋性增强。事实上，令人惊讶的是，关于背根神经节（DRG）的感觉神经元对脊髓损伤的反应知之甚少。提出的研究基于一种新的假设，即脊髓损伤触发伤害感受器的慢性功能亢进状态，导致DRGs的躯体内产生SA，这种持续的SA刺激中枢疼痛通路，导致自发性疼痛、异常性疼痛和痛觉过敏。将测试这一假说1)检查SCI对股价的影响和随后的DRG神经元的电生理特性和测试,2)检查SA在SCI后DRG神经元体内,和3)试图阻止SA(以及SCI疼痛相关),断开的DRG脊髓挫伤)前(背侧神经根切断术或击倒的几种Na +通道所必需的痛觉受器代SA。在标准挫伤模型中，脊髓损伤发生在脊髓水平T10。损伤后3天、1个月和3个月分别进行行为和电生理测试。行为测试将评估运动丧失和可能的恢复，以及（在1个月和3个月时）损伤水平以上和以下的自发性疼痛、异常性疼痛和痛觉过敏。采用全细胞电流箝法对游离于T9、T11和L4水平的DRG神经元进行体外电生理实验。除了记录SA外，一个复杂的测试方案将定义静息膜电位和-80 mV（电压门控钠通道失活很少）和-50 mV（许多通道失活）保持电位下的固有被动和主动膜特性。体内电生理测试将使用从背根提取的细丝的细胞外记录来观察DRG与外周断开前后的SA含量。将对功能亢进的伤害感受器假说的四个预测进行检验：首先，脊髓损伤应该增强假定的伤害性DRG神经元的SA，最初是在损伤水平以下，但后来也在损伤水平以上。其次，体外和体内SA的增强，以及体外的高兴奋性，应该与疼痛、异常性疼痛和痛觉过敏等行为体征的增强相关。第三，如果脊髓损伤疼痛部分依赖于伤害感受器中的SA，则应通过选择性抑制体内伤害感受器SA来减轻脊髓损伤疼痛。这将通过在鞘内递送反义寡核苷酸来降低Na+通道Nav1.8的表达来验证，Nav1.8在伤害性感觉神经元中选择性表达，是在这些神经元中产生SA所必需的。第四，在脊髓损伤发生前立即进行背侧神经根切断术，以验证从这些神经元的中枢突向伤害感受器体的逆行信号是触发SA所必需的假设。这些探索性研究将测试一个关于脊髓损伤疼痛重要机制的新假设，定义与神经性疼痛相关的DRG神经元的内在电生理改变，并开始测试一种可能对治疗脊髓损伤疼痛有用的干预措施。公共卫生相关性：脊髓损伤患者经常遭受使人衰弱的疼痛，这种疼痛对临床治疗有很高的抵抗力。尽管对这一问题的大多数研究都集中在疼痛通路中中枢神经元的改变上，但初步数据表明，通常从外周组织传递疼痛信息的感觉神经元的改变可能起重要作用。拟议的研究将检验一种假设，即脊髓损伤引起的慢性疼痛部分是由感觉神经元的自发电活动产生的，并且可以通过阻断这种活动来减轻疼痛。