Neuronal plasticity at remote sites causes neuropathic pain after SCI

描述（由申请人提供）：脊髓损伤（SCI）通常损害感觉系统，引起慢性异常性疼痛和痛觉过敏，这是两种常见的神经性疼痛形式。虽然运动系统的恢复似乎与震中的轴突保留呈指数相关，但正常感觉的恢复似乎是全或无反应。在挫伤性SCI模型中，发生严重的超敏反应，在病变中心有超过90%的轴突损失，并且在强度上与经典的外周神经损伤模型中产生的疼痛相似。周围神经损伤（PNI）后神经病理性疼痛的发生机制已被广泛研究，而中枢创伤后疼痛发生的机制尚不清楚。最近的研究表明，脊髓损伤后下行运动系统的新重塑引起了深刻的运动恢复。使用类似的跨突触标记和功能磁共振成像技术，我们将确定上行疼痛通路的解剖完整性或新的可塑性。我们实验室的初步数据表明，深刻的小胶质细胞激活不仅发生在脊髓损伤尾侧的浅表背角10节段内，而且与脊髓损伤后慢性超敏反应的发展密切相关。虽然这些数据表明，神经胶质细胞在SCI后超敏反应的发展中发挥了重要作用，但它也表明，由于神经胶质细胞-神经元通信和/或感觉处理发生的局部环境的改变，可能对感觉神经元产生深远的影响。本提案的目的是确定脊髓损伤后发生的感觉变化是否是脊髓上区域远离病变部位发生的解剖和功能变化的结果，这些区域参与疼痛和感觉信息的处理，如丘脑腹后外侧核。这些区域的潜在变化可能最终导致超敏反应或疼痛感知。这一提议将首次表明存在一种解剖学和功能性通路（无论是原始的备用通路还是新的通路），它在SCI后传递疼痛和感觉信息。这将为未来的机制研究提供基础，最终导致更好，更有效的治疗人类SCI后发生的神经性疼痛。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) often impairs sensory systems causing chronic allodynia and hyperalgesia, two common forms of neuropathic pain. While the recovery of motor systems appears to be exponentialy related to axonal sparing at the epicenter, the recovery of normal sensation appears to be an all or none response. In contusion SCI models, profound hypersensitization occurs with greater than 90% axonal loss at the lesion epicenter and is similar in intensity to the pain produced in classic peripheral nerve injury models. The mechanism of neuropathic pain development has been studied extensively following peripheral nerve injury (PNI), while little is known about the mechanism underlying pain development after central trauma. Recent studies show novel remodeling of descending motor systems after SCI that elicited profound locomotor recovery. Using similar transynaptic labeling and functional magnetic resonance imaging techniques, we will determine the anatomical integrity or novel plasticity of the ascending pain pathways. Preliminary data from our laboratory suggest that profound microglial activation not only occurs within the superficial dorsal horn ten segments caudal to the SCI lesion, but also correlates strongly to the development of chronic hypersensitivity after SCI. Though these data suggest that glia play a significant role in the development of hypersensitivity after SCI, it also suggests that there may be profound effects on the sensory neurons due to glial-neuronal communication and/or an alteration of the local environment where sensory processing occurs. The purpose of this proposal is to ascertain whether sensory changes that occur after spinal cord injury are a result of anatomical and functional changes that occur away from the lesion site in supraspinal regions that are involved in the processing of pain and sensory information such as the ventroposterolateral nucleus of the thalamus Potential changes in these regions may ultimately cause hypersensitivity or the perception of pain. This proposal would show for the first time an anatomical and functional pathway (either the original spared or novel pathway) exists that relays pain and sensory information after SCI. It will provide a basis for targeting future mechanistic studies which will ultimately lead to better, more efficacious treatments for the neuropathic pain which occurs after human SCI.