Acute Neurogenic Inflammation

炎性疼痛形成许多疾病的主要症状，并且常常使疾病复杂化并干扰其治疗。炎症反应的主要原因是外周组织损伤，其中多种内源性化学试剂从受损细胞、免疫细胞和受损神经末梢释放。 炎症被认为是由神经源性成分，其中涉及小的有髓和无髓的伤害性初级传入纤维的效应器功能启动。由于外周组织损伤，血管活性肽从这些末端释放有助于神经源性炎症的发展。 越来越多的研究表明初级传入纤维的效应器作用是通过背根反射（DRR）中枢介导的。 另一方面，交感传出神经可能通过与初级传入末梢的相互作用来调节炎症性疼痛。 我们推测，由DRR产生引起的神经源性炎症部分取决于交感神经-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是否受到交感传出神经的调制以及交感神经调制发生的位置。皮内注射辣椒素（CAP）可诱发急性皮肤炎症。 将使用麻醉大鼠中初级传入纤维的传入和传出活动的多单位或单单位记录以及皮肤血流量测量来检验假设：1.完整的交感神经传出对于皮内注射CAP后伤害感受器的敏化是必不可少的。 由于伤害感受器的敏化而增加的传入阻滞然后将通过脊髓回路触发DRR（具体目标1、2和3）; 2. CAP注射后DRR的产生至少部分依赖于增强的交感神经节后传出活性，其将通过释放去甲肾上腺素、神经肽Y（NPY）或腺苷5 '-三磷酸以激活外周α-肾上腺素能、NPY或嘌呤能受体而使伤害感受器敏感。（具体目标4）。 这些研究的长期目标是了解交感神经-感觉相互作用如何影响DRR的产生，进而调节神经源性炎症。 因此，该项目将提供有关炎症性疼痛机制的重要新信息，这无疑将有助于我们更好地了解炎症相关疼痛。 显然，这些信息也将提供有价值的洞察力的潜在治疗价值的药物在管理神经源性炎性疼痛。

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.