PERSISTENT PAIN: PERIPHERAL AND CNS MECHANISMS

“疼痛对所有美国人的生活质量和健康相关成本产生了深远的影响。每年花费美国公众超过1000亿美元的医疗保健，赔偿和诉讼”（来自NIH指南疼痛研究新方向）。长期暴露于疼痛刺激会引起神经系统的变化，这是慢性疼痛的原因。这些变化很难逆转。慢性疼痛对受其影响的个体来说是衰弱的，并且对大多数治疗是难治的。我们小组的目标是通过研究由持续性伤害感受引发的外周神经和脊髓机制，进一步确定介导损伤后观察到的疼痛持续变化的细胞机制。这是一个复杂的过程，涉及支持组织、免疫系统、躯体和自主神经系统以及所有细胞外和细胞内信使系统的相互作用。如此多不同系统的相互作用使得理解这一过程变得复杂，需要多学科团队的方法来实现最佳进展。利用项目机制，我们建议组建这样一个团队。项目1（PI，Alan Light）将研究星形胶质细胞和小胶质细胞被有害的外周输入激活的机制，以及这些细胞如何与神经元相互作用以介导疼痛反应的长期行为变化。项目2（PI，Lorne Mendell）将利用体外记录方法来检查神经生长因子使大鼠DRG中伤害感受神经元的反应敏感的机制，并确定炎症如何改变这种机制。这些研究还将解决伤害感受器对不同神经营养素的反应的特异性、它们的作用的时间过程以及神经营养素与其他物质（例如，5-羟色胺）已知激活或敏感的伤害性传入。项目3（PI，Gerry Oxford）将研究生长因子、细胞内调节剂和新克隆的香草素受体相互作用在大鼠背根神经节细胞中产生致敏作用的分子机制。

"Pain has a profound impact on the quality of life and health-associated costs for all Americans...costing the American public more than $100 billion each year in health care, compensation and litigation"(from NIH Guide New directions in Pain Research). Long-term exposure to painful stimuli can elicit changes in the nervous system that are the cause of chronic pain. These changes can be very difficult to reverse. Chronic pain is debilitating for those individuals it affects, and is refractory to most treatments. The goal of our group is to further determine the cellular mechanisms that mediate the persistent alterations in pain observed following injury, by studying both the peripheral nerve and the spinal cord mechanisms initiated by persistent nociception. This is a complex process involving interactions of supporting tissues, the immune system, the somatic and autonomic nervous systems, and all of the extracellular and intracellular messenger systems. The interaction of so many diverse systems makes understanding this process complex and requires a multi-disciplinary team approach for optimal progress. Using the Program Project Mechanism, we propose to form such a team. Project 1 (PI, Alan Light) will study the mechanisms by which astrocytes and microglia become activated by noxious peripheral inputs and how these cells interact with neurons to mediate long-term behavioral changes in pain responses. Project 2 (PI, Lorne Mendell) will make use of in vitro recording methods to examine the mechanisms by which nerve growth factor sensitizes the responses of nociceptive neurons in rat DRG and to determine how this is modified by inflammation. These studied will also address the specificity of the response of nociceptors to different neurotrophins, the time course of their action and the interaction of neurotrophins with other substances (e.g., serotonin) known to activate or sensitive nociceptive afferents. Project 3 (PI, Gerry Oxford) will study the molecular mechanisms by which growth factors, intracellular modulators, and the newly cloned vanilloid receptor interact to produce sensitization in rat dorsal root ganglion cells.