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首页> 外文期刊>Pain. >A novel intrinsic analgesic mechanism: the enhancement of the conduction failure along polymodal nociceptive C-fibers
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A novel intrinsic analgesic mechanism: the enhancement of the conduction failure along polymodal nociceptive C-fibers

机译：一种新颖的内在镇痛机制：沿多峰伤害性C纤维的传导失败的增强

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Although conduction failure has been observed in nociceptive C-fibers, little is known regarding its significance or therapeutic potential. In a previous study, we demonstrated that C-fiber conduction failure, which is regarded as an intrinsic self-inhibition mechanism, was reduced in circumstances of painful diabetic neuropathy. In this study, we extend this finding in the complete Freund's adjuvant model of inflammatory pain and validate that the degree of conduction failure decreased and led to a greater amount of pain signals conveyed to the central nervous system. In complete Freund's adjuvant-injected animals, conduction failure occurred in a C-fiber-selective, activity-dependent manner and was associated with an increase in the rising slope of the C-fiber after-hyperpolarization potential. To target conduction failure in a therapeutic modality, we used ZD7288, an antagonist of hyperpolarization-activated, cyclic nucleotide-modulated channels which are activated by hyperpolarization and play a pivotal role in both inflammatory and neuropathic pain. ZD7288 promoted conduction failure by suppressing I-h as a mechanism to reduce the rising slope of the after-hyperpolarization potential. Moreover, perineuronal injection of ZD7288 inhibited abnormal mechanical allodynia and thermal hyperalgesia without affecting motor function or heart rate. Our data highlight the analgesic potential of local ZD7288 application and identify conduction failure as a novel target for analgesic therapeutic development.
机译：尽管在伤害性C纤维中已观察到传导失败，但对其重要性或治疗潜力知之甚少。在先前的研究中，我们证明了在疼痛性糖尿病性神经病的情况下，C纤维传导衰竭（一种固有的自我抑制机制）得以减少。在这项研究中，我们在炎性疼痛的完整弗氏佐剂模型中扩展了这一发现，并验证了传导衰竭的程度降低并导致了传递到中枢神经系统的大量疼痛信号。在完全弗氏佐剂注射的动物中，传导失败以C纤维选择性，活动依赖的方式发生，并且与超极化后C纤维的上升斜率增加有关。为了针对治疗模式中的传导失败，我们使用了ZD7288，它是超极化激活的环状核苷酸调节通道的拮抗剂，该通道被超极化激活，在炎症性疼痛和神经性疼痛中起关键作用。 ZD7288通过抑制I-h作为降低超极化后电位上升斜率的机制来促进传导失败。此外，ZD7288的神经尿素注射可抑制异常的机械性异常性疼痛和热痛觉过敏，而不会影响运动功能或心率。我们的数据突出了局部ZD7288应用的镇痛潜力，并将传导失败确定为镇痛治疗发展的新目标。

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