NEUROCHEMISTRY OF NOCICEPTION

描述：(申请人摘要) 慢性疼痛综合征的管理是一个巨大的挑战 随着当前疼痛管理接近麻醉药物，医学领域 作为吗啡，会带来副作用，如镇静、便秘、 宽容和上瘾。因此，更好地理解 需要导致慢性疼痛状态的病理生理机制 用于开发副作用最小的新型有效疗法。 最近，我们证明了当P物质(SP)和 核糖体失活蛋白Saporin(SAP)被注入脊髓， SP-SAP结合物对I层具有特异性内化和细胞毒性作用 表达P物质受体(SPR)的脊髓神经元。这 治疗使对轻微有害刺激的反应保持不变，但影响深远 减弱对高度有害刺激以及对机械和热刺激的反应 痛觉过敏。 大鼠脊髓鞘内注射SP-SAP作为动物模型 我们建议：研究这种治疗方法是否可以缓解 炎症性和/或神经性持续性疼痛状态(目标1)；进一步 确定这些神经元投射到的头端大脑区域和另一个 I层表达的受体和神经递质 表达SPR的神经元(目标2)；确定神经元的功能作用 在伤害性加工和痛觉过敏中表达SPR，以及是否 这些表达SPR的神经元在功能上不同于伤害性感受 不表达SPR的神经元(目标3)；并确定 脊髓和背根神经节的重组发生在 SP-SAP治疗与吗啡是否仍能有效缓解 伤害性反应(目标4)。来自这些调查的信息将 对脊髓伤害性感受器的神经化学有重要的洞察力 信号转导与SP-SAP治疗是否具有发展前景 控制人类慢性疼痛的非阿片类药物治疗。

Description: (Applicant's Abstract) Management of chronic painful syndromes presents a tremendous challenge to the medical field as current pain management approaches with narcotics, such as morphine, carry adverse side effects such as sedation, constipation, tolerance and addiction. Therefore, a greater understanding of pathophysiological mechanisms that lead to a chronic pain state is needed for development of novel and effective therapies with minimal side effects. Recently, we demonstrated that when a conjugate of substance P (SP) and the ribosome-inactivating protein saporin (SAP) is infused into the spinal cord, the SP-SAP conjugate is specifically internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor (SPR). This treatment leaves responses to mild noxious stimuli unchanged, but profoundly attenuates responses to highly noxious stimuli and to mechanical and thermal hyperalgesia. Using the intrathecal infusion of SP-SAP in the rat spinal cord as our model we propose: to investigate whether this treatment can alleviate inflammatory and/or neuropathic persistent pain states (Aim 1); to further define the rostral brain areas these neurons project to and the other receptors and neurotransmitters that are expressed by lamina I SPR-expressing neurons (Aim 2); to determine the functional role of neurons that express the SPR in nociceptive processing and hyperalgesia, and whether these SPR expressing neurons are functionally different from nociceptive neurons that do not express the SPR (Aim 3); and to determine whether reorganization of the spinal cord and dorsal root ganglia occurs following SP-SAP treatment and whether morphine is still effective in attenuating nociceptive responses (Aim 4). Information from these investigations will provide significant insight into the neurochemistry of spinal nociceptive signaling and whether SP-SAP treatment shows promise for developing non-opioid therapies to control chronic pain in humans.