ANTIBODY NOCICEPTOR SENSITIZATION & ALLOYDNIA

最近的观察表明，抗体-抗原反应沿着 感觉轴突，如在识别抗GD2之后发生的 抗体为其膜成分抗原，可导致补体 肿瘤坏死因子-a的固定和相关的局部释放 (肿瘤坏死因子)来自肥大细胞和雪旺细胞。肿瘤坏死因子形成膜NA 孔洞提供了一种启动异位去极化的新机制 非终末部位的轴突。感官处理的这种变化是 不依赖于外周受体或轴突的结构变化。 全身注射抗GD2作为免疫治疗剂， 会导致人类剧烈疼痛和超感痛觉。痛觉过敏可以是 以大鼠为模型：注射抗GD2抗体可导致 传入纤维的持续活动以及伤害性感受器的敏化。 在许多疼痛状态下，内源性肿瘤坏死因子在神经内释放， 包括局部炎症和损伤。肿瘤坏死因子的局部给药 刺激神经干也可引起伤害性传入的放电。 频率与中枢敏感化的发展相一致。 这项提议将调查一种假说，即一种GD2抗体 伤害性感觉的改变是由启动的免疫反应引起的 外周伤害性轴突的病例。的行为反应 用抗GD2抗体对一系列皮肤刺激进行治疗的大鼠 量过了。将测试机械性痛觉过敏和热痛觉过敏。 PAN状态对补体结合、前列腺素和 将探索细胞因子的释放。正在进行的活动和感觉 将为所识别的初级传入纤维记录阈值， 专注于被认为传递疼痛信息的A和C纤维。 用于检查生成的相同变量的操作 行为疼痛状态将用作录制前的预处理 神经纤维的兴奋性。通过这种方式，疼痛之间的平行变化 将对行为和电生理学进行评估。肿瘤坏死因子、前列腺素和 局部酸度的增加将直接作用于神经。 以确定这些物质是否足以引发 卡斯卡德。结果将开始描绘药理序列 注射GD2抗体引起疼痛的事件。 这项工作将是确定中轴突是否产生的第一步 由肿瘤坏死因子介导的传入吞吐量增加是一种常见的 与组织和神经相关的病理性疼痛状态中的元素 受伤。沿着轴突的这一系列事件从根本上代表了 解释多种异常疼痛产生的不同方式 并因此可以开始开发新的方法来 治疗。

Recent observations suggest that antibody-antigen reactions along sensory axons, such as occurs following recognition of the anti-GD2 antibody for it membrane constituent antigen, may lead to complement fixation and an associated local release of tumor necrosis factor-a (TNF) from mast cells and Schwann cells. TNF forms membrane na+ pores providing a novel mechanism for initiating ectopic depolarization of axons at non terminal sites. This alteration in sensory processing is independent of peripheral receptors or structural changes of the axon. Systemic administration of antiGD2, as an immunotherapeutic agent, leads to severe pain and allodynia in man. Thia allodynia can be modeled in rats: administration of anti-GD2 antibody results in ongoing activity in afferent fibers as well as nociceptor sensitization. Endogenous TNF is released within nerves in many pain states, including local inflammation and injury. focal administration of TNF to the nerve trunk also elicits discharge in nociceptive afferents at frequencies consistent with the development of central sensitization. This proposal will investigate the hypothesis that anitGD2 antibody alterations of nociception are induced by an immune response initiated case along the peripheral nociceptive axons. Behavioral responses of rats treated with anti-GD2 to a range of cutaneous stimuli will be measured. Mechano-allodynia and thermal hyperalgesia will be tested. Dependence of the pan state on complement fixation, prostanoids and cytokine release will be explored. Ongoing activity and sensory thresholds will be recorded for identified primary afferent fibers, concentrating on A and C fibers thought to transmit pain information. Manipulations of the same variables used to examine generation of behavioral pain states will be used as pretreatments before recording excitability of nerve fibers. In this way, parallel changes between pain behavior and electrophysiology will be assessed. TNF, prostanoids and local increases in acidity will be administered directly to the nerve trunk to ascertain if these substances are sufficient to trigger the cascade. Results will begin to delineate the pharmacological sequence of events by which administration of GD2 antibody produces pain. This work will be the first step in determining if mid axonal generation of increased afferent throughput, mediated by TNF, is a common element in pathological pain states associated with tissue and nerve injury. This series of events along the axon represents a fundamentally different way for explaining the generation of many anomalous pain states and may thus initiate development of novel approaches to treatment.