Acute Neurogenic Inflammation

炎症性疼痛是许多疾病的主要症状，常常使疾病复杂化并妨碍其治疗。炎症反应的主要原因是外周组织损伤，受损细胞、免疫细胞和受损神经末梢释放出多种内源性化学物质。炎症被认为是由神经源性成分发起的，这涉及到小髓鞘和无髓鞘伤害初级传入纤维的效应功能。由于外周组织损伤，血管活性肽从这些末梢释放有助于发生神经源性炎症。越来越多的研究表明，初级传入纤维的效应作用是通过背根反射（DRRs）中枢介导的。另一方面，交感传入神经已被证明可能通过与初级传入终端的相互作用来调节炎性疼痛。我们假设，由DRRs产生的神经源性炎症部分取决于交感-感觉相互作用。拟议的研究将检查drr介导的皮肤神经源性炎症和drr是否受到交感神经传出的调节，以及交感神经调节发生在哪里。皮内注射辣椒素可引起急性皮肤炎症。麻醉大鼠的主要传入纤维的传入和传出活动的多单元或单单元记录和皮肤血流量测量将用于验证假设：皮内注射CAP后，完整的交感神经输出对于伤害感受器的敏化至关重要。伤害感受器敏化导致的传入弹障增加将通过脊髓回路触发DRRs (Specific Aims 1、2和3)；2. CAP注射后DRRs的产生至少部分依赖于交感神经节后输出活动的增强，该活动通过释放去甲肾上腺素、神经肽Y （NPY）或5'-三磷酸腺苷激活外周α -肾上腺素能、NPY或嘌呤能受体，使伤害感受器敏感。（具体目标4）。这些研究的长期目标是了解交感-感觉相互作用如何影响DRRs的产生，进而调节神经源性炎症。因此，该项目将提供炎症性疼痛机制的重要新信息，无疑将帮助我们更好地理解炎症相关疼痛。显然，这些信息也将为神经源性炎症性疼痛治疗药物的潜在治疗价值提供有价值的见解。

Inflammatory pain forms a major symptom in many diseases and often complicates the disease and disturbs its treatment. The major causes of inflammatory responses are peripheral tissue injuries where a variety of endogenous chemical agents are released from damaged cells, immune cells and injured nerve terminals. Inflammation is suggested to be initiated by the neurogenic component, which involves the effector function of small myelinated and unmyelinated nociceptive primary afferent fibers. Release of vasoactive peptides from these terminals due to injury to peripheral tissue helps develop neurogenic inflammation. An increasing number of studies demonstrate that the effector action of primary afferent fibers is centrally mediated by way of dorsal root reflexes (DRRs). On the other hand, sympathetic efferents have been shown to modulate inflammatory pain possibly by interaction with primary afferent terminals. We hypothesize that neurogenic inflammation resulting from the generation of DRRs depends in part on a sympathetic- sensory interaction. The proposed studies will examine if DRR-mediated cutaneous neurogenic inflammation and DRRs are modulated by sympathetic efferents and where the sympathetic modulation takes place. Acute cutaneous inflammation will be evoked by intradermal injection of capsaicin (CAP). Multi- or single-unit recordings of afferent and efferent activity of primary afferent fibers and cutaneous blood flow measurements in anesthetized rats will be used to test the hypotheses: 1. Intact sympathetic efferents are essential for the sensitization of nociceptors following intradermal injection of CAP. The increased afferent barrage due to sensitization of nociceptors would then trigger DRRs through spinal circuits (Specific Aims 1, 2 and 3); 2. Generation of DRRs following CAP injection is, at least, partially dependent on the enhanced sympathetic postganglionic efferent activity that would sensitize nociceptors by releasing norepinephrine, neuropeptide Y (NPY) or adenosine 5'-triphosphate to activate peripheral alpha- adrenergic, NPY, or purinergic receptors. (Specific Aim 4). The long-term goal of these studies is to learn how sympathetic- sensory interactions affect the generation of DRRs and, in turn, modulate neurogenic inflammation. Therefore, this project will provide important new information on inflammatory pain mechanisms that will doubtless help us understand inflammation-related pain better. Obviously, this information will also provide valuable insight into the potential therapeutic value of drugs in management of neurogenic inflammatory pain.