Injury Induced Facilitated Neurogenic Inflammation

骨折和神经损伤可导致复杂的区域疼痛综合征(CRPS)。该综合征具有一系列令人费解的临床表现，包括皮肤血流量增加、皮肤温度升高、自发性蛋白外渗、四肢浮肿、关节周围骨质减少、自发性疼痛、痛觉过敏和痛觉异常。这种病理生理机制尚不清楚，大多数有持续性症状的CRPS患者都是永久性残疾的。这一建议检验了这样一种假设，即在人类中最常见的导致CRPS I型(肢体远端骨折)和II型(不完全神经损伤)的损伤在大鼠中会引起类似的症状，包括皮肤血管功能的变化(皮肤温度升高、血管扩张和自发外渗)、骨组织(通过X光片和吸收测量法测量的关节周围骨量减少)和伤害性阈值(后爪痛觉过敏和痛觉过敏)。在确定骨折和不完全性神经损伤大鼠模型类似于CRPS I型和II型之后，下一步将检验促进P物质信号转导在这些损伤模型中观察到的血管、骨骼和伤害性变化的假说。为了证实这一假设，P物质神经元的神经毒性损伤将用于防止损伤模型中血管、骨骼和伤害性变化的发展，而P物质受体拮抗剂将用于逆转这些模型的CRPS病理生理。最后，这项建议将利用CRPS模型来开发用于测量易化皮肤神经源性炎症反应的有创和非侵入性技术，该技术可用于未来研究CRPS患者的易化P物质信号转导。这些技术包括使用皮肤微透析和激光多普勒血流测量来确定蛋白质外渗和血管扩张对电刺激和P物质微量注射的反应。一种侵入性较小的方法将使用P物质的皮肤离子导入来激发激光多普勒测量的促进血管扩张反应。在这些研究过程中收集的信息将极大地有助于我们理解促进P物质信号在血管、骨骼和伤害性CRPS后遗症中的作用，并将有助于提高这些不同损伤后果的药物管理的有效性和安全性的最终目标。

Fractures and nerve injuries can lead to the development of a complex regional pain syndrome (CRPS). This syndrome presents with a baffling array of clinical findings, including increased cutaneous blood flow, increased skin temperature, spontaneous protein extravasation, limb edema, periarticular osteopenia, spontaneous pain, hyperalgesia and allodynia. The mechanism underlying this pathophysiology is unknown and most CRPS patients with persistent symptoms are permanently disabled. This proposal tests the hypothesis that the injuries that most frequently cause CRPS Type I (distal limb fractures) and Type II (incomplete nerve injuries) in man evoke similar syndromes in rats, including changes in cutaneous vascular function (increased skin temperature, vasodilatation, and spontaneous extravasation), bony tissue (periarticular osteopenia measured by radiographs and absorptiometry), and nociceptive thresholds (hindpaw hyperalgesia and allodynia). After establishing that the fracture and incomplete nerve injury rat models resemble CRPS Type I and II, the next step will be to test the hypothesis that facilitated substance P signaling mediates the vascular, bony and nociceptive changes observed in these injury models. To confirm this hypothesis, neurotoxic lesioning of the substance P containing neurons will be used to prevent the development of vascular, bony, and nociceptive changes in the injury models, while substance P receptor antagonists will be used to reverse CRPS pathophysiology in these models. Finally, this proposal will utilize the CRPS models to develop invasive and noninvasive techniques for measuring facilitated cutaneous neurogenic inflammatory responses, techniques which can be used in future investigations examining facilitated substance P signaling in CRPS patients. These techniques include using cutaneous microdialysis and laser Doppler blood flow measurements to determine protein extravasation and vasodilatation responses to electrical stimulation and substance P microinfusion. A less invasive method will use cutaneous iontophoresis of substance P to evoke a facilitated vasodilatation response measured by laser Doppler. The information collected during the course of these studies will greatly contribute to our understanding of the role of facilitated substance P signaling in the vascular, bony, and nociceptive CRPS sequelae, and will contribute to the ultimate goal of improving the efficacy and safety of the pharmacologic management of these diverse consequences of injury.