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，导致慢性痛觉异常和痛觉过敏，这是神经性疼痛的两种常见形式。虽然运动系统的恢复似乎与震中轴突的保留呈指数级相关，但正常感觉的恢复似乎是一种全有或无反应。在挫伤脊髓损伤模型中，损伤中心90%以上的轴突丢失，发生严重的超敏反应，其强度与经典的周围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，而对中枢创伤后疼痛发生的机制知之甚少。最近的研究表明，脊髓损伤后下行运动系统的新的重塑导致了深刻的运动恢复。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，深层次的小胶质细胞激活不仅发生在脊髓损伤尾侧的背角浅层10个节段，而且与脊髓损伤后慢性超敏反应的发展密切相关。虽然这些数据表明胶质细胞在脊髓损伤后超敏反应的发生发展中起重要作用，但也表明可能由于神经胶质细胞与神经元的通讯和/或感觉加工发生的局部环境的改变而对感觉神经元产生深刻的影响。这一建议的目的是确定脊髓损伤后发生的感觉变化是否是脊柱上区域发生的解剖和功能变化的结果，这些区域发生的解剖和功能变化涉及疼痛的处理和感觉信息，如丘脑腹后外侧核，这些区域的潜在变化最终可能导致超敏或痛觉。这一提议将首次表明，脊髓损伤后存在一种解剖和功能通路(无论是原始的备用通路还是新的通路)，传递疼痛和感觉信息。这将为未来有针对性的机制研究提供基础，最终将导致更好、更有效的治疗人类脊髓损伤后神经病理性疼痛的方法。

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.