Department of Orthopedics, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China.
Pain and Related Diseases Research Laboratory, Medical College of Shantou University, Shantou, 515041, China.
Neurosci Bull. 2023 Dec;39(12):1789-1806. doi: 10.1007/s12264-023-01075-0. Epub 2023 Jun 19.
Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.
臂丛神经撕脱伤（Brachial plexus avulsion，BPA）是一种涉及中枢和外周神经系统的联合损伤。BPA 患者常出现受累肢体严重的神经性疼痛（neuropathic pain，NP）。NP 对现有治疗方法不敏感，这给研究人员和临床医生带来了挑战。大量证据表明，BPA 诱导的疼痛状态常伴有交感神经功能障碍，这表明交感神经系统的兴奋状态与 NP 的存在相关。然而，外周水平感觉神经与交感神经的串扰机制尚不清楚。在这项研究中，我们通过使用一种新的 C7 神经根撕脱 BPA 小鼠模型，发现 BPA 小鼠的背根神经节（DRG）中 BDNF 及其受体 TrkB 的表达增加，交感神经活性标志物包括α1 和 α2 肾上腺素能受体（α1-AR 和 α2-AR）在 BPA 后也增加。通过 CatWalk 步态分析、红外温度计和水肿评估，我们还观察到 BPA 小鼠出现交感神经超兴奋现象，包括患侧肢体发冷和水肿。DRG 中 BDNF 的基因敲低不仅逆转了机械性痛觉过敏，还缓解了 BPA 小鼠患侧肢体的发冷和水肿。此外，腹腔内注射肾上腺素能受体抑制剂降低了在膜片钳记录中的神经元兴奋性，并逆转了 BPA 小鼠的机械性痛觉过敏。在另一个分支实验中，我们还通过 Western blot 和免疫组织化学发现 BPA 患者的 DRG 组织中 BDNF、TrkB、TH、α1-AR 和 α2-AR 的表达升高，与正常人的 DRG 相比。我们的结果表明，外周 BDNF 是调节 BPA 诱导的 NP 中感觉-交感耦合的关键分子。这项研究还为这种疼痛的治疗开辟了一个新的镇痛靶点（BDNF），具有较少的并发症，具有很大的临床转化潜力。
