Bechakra Malik, Schüttenhelm Barthold N, Pederzani Tiziana, van Doorn Pieter A, de Zeeuw Chris I, Jongen Joost L M
Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
J Comp Neurol. 2017 Dec 1;525(17):3757-3768. doi: 10.1002/cne.24302. Epub 2017 Aug 30.
Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide, a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia.
神经性疼痛患者的皮肤活检通常显示表皮神经支配发生变化，尽管这种变化在多大程度上与特定的神经纤维亚组相关以及这些变化如何与疼痛强度相关仍有待阐明。在此，我们研究了在神经损伤诱导的疼痛大鼠模型中，痛觉过敏的行为体征与肽能和非肽能表皮神经纤维的免疫组化变化在多大程度上相关。通过同侧足垫对von Frey毛发和热板刺激的退缩反应测试，接受坐骨神经单侧部分结扎的大鼠出现了明显的机械性和热性痛觉过敏。在第14天，经两名盲法观察者测试和重新测试后，与对侧相比，表皮神经纤维密度和每毫米表皮神经纤维总长度均显著且持续降低。肽能神经纤维标记物降钙素基因相关肽的表达在同侧没有显著变化。相比之下，非肽能神经纤维标记物P2X受体的表达不仅显著降低，而且还与行为性痛觉过敏相关。当用泛神经元标记物PGP9.5标记肽能和非肽能神经纤维时，其表达显著降低，尽管与行为性痛觉过敏没有显著相关性。综合来看，我们的数据表明P2X表皮神经纤维的病理变化可以选择性地与神经病变相关联，这突出了这些纤维的退化驱动痛觉过敏的可能性。
