NEUROCHEMISTRY OF NOCICEPTION

描述：（申请人摘要） 慢性疼痛综合征的管理对患者提出了巨大的挑战， 医疗领域，如目前的疼痛管理方法与麻醉剂，如 如吗啡，具有不良副作用，如镇静，便秘， 宽容和成瘾。 因此，更好地理解 需要导致慢性疼痛状态的病理生理机制 用于开发新的和有效的治疗方法，副作用最小。 最近，我们证明，当P物质（SP）和 将核糖体失活蛋白皂草素（SAP）注入脊髓， SP-SAP缀合物特异性内化并对层I具有细胞毒性 表达P物质受体（SPR）的脊髓神经元。 这 治疗使对轻度伤害性刺激的反应保持不变， 减弱对高度伤害性刺激以及机械和热刺激的反应 痛觉过敏 以大鼠脊髓鞘内注射SP-SAP为模型， 我们建议：研究这种治疗是否能减轻 炎性和/或神经性持续疼痛状态（目的1）;进一步 定义这些神经元投射到的嘴侧大脑区域， I层表达的受体和神经递质 SPR表达神经元（目的2）;确定神经元的功能作用 在伤害性处理和痛觉过敏中表达SPR，以及是否 这些SPR表达神经元在功能上不同于伤害感受神经元， 不表达SPR的神经元（目的3）;并确定是否 脊髓和背根神经节的重组发生在 SP-SAP治疗和吗啡是否仍然有效地减轻 伤害性反应（目的4）。 这些调查的信息将 提供了对脊髓伤害性神经化学的重要见解， 信号传导以及SP-SAP治疗是否显示出发展 非阿片类药物治疗来控制人类的慢性疼痛。

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.