Wang Guojun, Dai Dawei, Chen Xin, Yuan Lei, Zhang Aijun, Lu Youming, Zhang Pengqi
Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China ; Department of Neurosurgery, Central Hospital of Tai'an Tai'an, Shandong Province, China.
Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
Int J Clin Exp Pathol. 2014 Aug 15;7(9):5916-21. eCollection 2014.
Peripheral nerve injury can result in neuropathic pain, a chronic condition of unclear cause often poorly responsive to current treatments. One possibility is that nerve injury disrupts large A-fiber-mediated inhibition of C-fiber-evoked responses in spinal dorsal horn neurons, leading to central sensitization. A recent study provided a potential molecular mechanism; large dorsal root ganglion (DRG) neurons secrete neuregulin-1 (NRG1), which binds to erbB4 receptors on interneurons and promotes GABA release to inhibit C-fiber-evoked nociceptive transmission. Thus, reduced NRG1 expression following nerve injury could induce chronic pain by disinhibition. We examined if DRG expression of NRG1 is in fact reduced in a rat model of neuropathic pain and if exogenous NRG1 alleviates behavioral signs of this condition.
Three neuropathic pain models were established in rats: spared nerve injury of the tibial and common peroneal nerves (SNI model), intraplantar injection of complete Freund's adjuvant (CFA model), and subcutaneous formalin injection. NRG1 expression was assessed by immunofluorescent staining, hyperalgesia by paw withdrawal threshold to von Frey filament stimulation, and pain-like behavior by spontaneous flinching.
NRG1 protein immunoreactivity was reduced in the rat DRG after SNI. Intrathecal administration of neuregulin-1beta 1 (NRG1-1), a 62 amino acid NRG1 mimetic, transiently increased paw withdrawal threshold in SNI model and reduced flinching in the formalin injection model.
Our results are consistent with a model of neuropathic pain whereby peripheral nerve injury reduces NRG1-mediated inhibition of nociceptive signaling. Modulating NRG1 may have therapeutic potential for treating neuropathic pain.
周围神经损伤可导致神经性疼痛，这是一种病因不明的慢性疾病，目前的治疗方法往往效果不佳。一种可能性是神经损伤破坏了脊髓背角神经元中由大 A 纤维介导的对 C 纤维诱发反应的抑制作用，从而导致中枢敏化。最近的一项研究提出了一种潜在的分子机制；大型背根神经节（DRG）神经元分泌神经调节蛋白-1（NRG1），其与中间神经元上的 erbB4 受体结合并促进 GABA 释放，以抑制 C 纤维诱发的伤害性传递。因此，神经损伤后 NRG1 表达降低可能通过去抑制作用诱发慢性疼痛。我们研究了在神经性疼痛大鼠模型中 DRG 中 NRG1 的表达是否实际上降低，以及外源性 NRG1 是否能减轻这种疾病的行为症状。
在大鼠中建立了三种神经性疼痛模型：胫神经和腓总神经的保留神经损伤（SNI 模型）、足底注射完全弗氏佐剂（CFA 模型）和皮下注射福尔马林。通过免疫荧光染色评估 NRG1 表达，通过对 von Frey 细丝刺激的爪退缩阈值评估痛觉过敏，并通过自发退缩评估疼痛样行为。
SNI 后大鼠 DRG 中 NRG1 蛋白免疫反应性降低。鞘内注射神经调节蛋白-1β1（NRG1-1），一种 62 个氨基酸的 NRG1 模拟物，在 SNI 模型中短暂提高了爪退缩阈值，并在福尔马林注射模型中减少了退缩。
我们的结果与神经性疼痛模型一致，即周围神经损伤会降低 NRG1 介导的对伤害性信号的抑制作用。调节 NRG1 可能具有治疗神经性疼痛的潜力。
