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）：摘要持续性神经性疼痛是由大多数患者的脊髓损伤（SCI）产生的。像其他形式的中枢神经性疼痛一样，SCI疼痛通常会使人衰弱，并且对临床治疗具有抗药性。关于SCI疼痛机制的大多数研究都集中在疼痛途径中中枢神经元的反应性和自发性电活动上，尤其是损伤部位附近背角的二阶神经元。 SCI后背角神经元的过度兴奋性似乎涉及许多合理的原因，但是几乎没有关注的原因是自发性活性（SA）的增强和兴奋性（尤其是伤害感受器）通常是激发背角神经元。确实，令人惊讶的是，关于背根神经节中的感觉神经元如何对SCI做出反应，知之甚少。拟议的研究基于以下新假设，即SCI在伤害感受器中触发了慢性过度官能状态，从而导致其在DRG中的somata中产生SA，并且这种持续的SA激发了中心疼痛途径，促进了自发的疼痛，异痛和痛苦。 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电压门控的Na+通道是伤害感受器生成SA所必需的。 SCI将在标准挫伤损伤模型中产生，并在脊柱级T10上产生影响。受伤后3天，1个月和3个月，行为和电生理测试将进行。行为测试将评估运动损失和可能的恢复，（在1和3个月时）自发疼痛，异常性症和痛觉过敏，在损伤水平之上和低于损伤水平。将使用与T9，T11和L4水平分离的DRG神经元的全细胞电流方法进行体外电生理测试。除记录SA外，复杂的测试方案还将定义静止膜电位和保持-80 mV的电位（在电压门控钠通道几乎没有失活）和-50 mV的固有的被动和主动膜特性和-50 mV（其中许多这些通道被灭活）。体内电生理测试将使用从背根嘲笑的细丝的细胞外记录，以查看从外围断开DRG之前和之后的SA存在多少。将测试对过度功能的伤害感受器假设的四个预测：首先，SCI应增强假定的伤害性DRG神经元的SA，最初是损伤水平及以下，但后来也高于损伤。其次，增强了体外和体内的SA，并且在体外过度兴奋，应与增强的疼痛，异常性和痛觉过敏的行为迹象相关。第三，如果SCI疼痛部分取决于伤害感受器中的SA，则应通过在体内选择性抑制伤害感受器SA来减轻SCI疼痛。这将通过固定的固定地输送反义寡核苷酸来测试，以击倒Na+通道Nav1.8的表达，该通道在伤害感受感官神经元中选择性表达，对于在这些神经元中产生SA是必不可少的。第四，对于触发SA的中心过程，必须通过在SCI前进行背侧根茎切开术来测试从这些神经元的中央过程中逆行信号逆行信号。这些探索性研究将检验一个关于对SCI疼痛重要的机制的新假设，定义了与神经性疼痛相关的DRG神经元中的内在电生理改变，并开始测试一种可能对治疗SCI疼痛有用的干预措施。公共卫生相关性：脊髓损伤患者通常会遭受对临床治疗高度抵抗力的疼痛。尽管对此问题的大多数研究都集中在疼痛途径中中枢神经元的变化上，但初步数据表明，通常从外周组织传达疼痛信息的感觉神经元的改变可能起重要作用。拟议的研究将检验以下假设：脊髓损伤引起的慢性疼痛部分是由于感觉神经元中自发的电活动产生的，并且可以通过阻断这种活性来减轻疼痛。