Long Juan, Liu Hongbing, Qiu Zhimin, Xiao Zhong, Lu Zhongqiu
Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou 325000, China.
Brain Sci. 2023 Apr 29;13(5):739. doi: 10.3390/brainsci13050739.
Patients undergoing bone fractures frequently suffer from irritating chronic pain after orthopedic repairs. Chemokine-mediated interactions between neurons and microglia are important steps for neuroinflammation and excitatory synaptic plasticity during the spinal transmission of pathological pain. Recently, glabridin, the main bioactive component of licorice, has been shown to exhibit anti-nociceptive and neuroprotective properties for inflammatory pain. This present study evaluated the therapeutic potential of glabridin and its analgesic mechanisms using a mouse model of tibial fracture-associated chronic pain. Repetitive injections of glabridin were delivered spinally daily for 4 continuous days from days 3 to 6 after the fractures. Herein, we discovered that repeated administrations of glabridin (10 and 50 μg, but not 1 μg) could prevent prolonged cold allodynia and mechanical allodynia following bone fractures. A single intrathecal intervention with glabridin (50 μg) relieved an existing chronic allodynia two weeks following the fracture surgeries. Systemic therapies with glabridin (intraperitoneal; 50 mg kg) were protective against long-lasting allodynia caused by fractures. Furthermore, glabridin restricted the fracture-caused spinal overexpressions of the chemokine fractalkine and its receptor CX3CR1, as well as the elevated number of microglial cells and dendritic spines. Strikingly, glabridin induced the inhibition of pain behaviors, microgliosis, and spine generation, which were abolished with the co-administration of exogenous fractalkine. Meanwhile, the exogenous fractalkine-evoked acute pain was compensated after microglia inhibition. Additionally, spinal neutralization of fractalkine/CX3CR1 signaling alleviated the intensity of postoperative allodynia after tibial fractures. These key findings identify that glabridin therapies confer protection against inducing and sustaining fracture-elicited chronic allodynia by suppressing fractalkine/CX3CR1-dependent spinal microgliosis and spine morphogenesis, suggesting that glabridin is a promising candidate in the translational development of chronic fracture pain control.
骨折患者在骨科修复后常遭受恼人的慢性疼痛。趋化因子介导的神经元与小胶质细胞之间的相互作用是病理性疼痛脊髓传导过程中神经炎症和兴奋性突触可塑性的重要步骤。最近，甘草的主要生物活性成分光甘草定已被证明对炎性疼痛具有抗伤害感受和神经保护特性。本研究使用小鼠胫骨骨折相关慢性疼痛模型评估了光甘草定的治疗潜力及其镇痛机制。骨折后第3天至第6天，每天连续4天经脊髓重复注射光甘草定。在此，我们发现重复给予光甘草定（10和50μg，但不是1μg）可以预防骨折后长期的冷痛觉过敏和机械性痛觉过敏。单次鞘内注射光甘草定（50μg）可缓解骨折手术后两周现有的慢性痛觉过敏。光甘草定全身治疗（腹腔注射；50mg/kg）对骨折引起的持久痛觉过敏具有保护作用。此外，光甘草定可抑制骨折引起的趋化因子fractalkine及其受体CX3CR1在脊髓中的过度表达，以及小胶质细胞数量和树突棘的增加。引人注目的是，光甘草定诱导了疼痛行为、小胶质细胞增生和脊柱生成的抑制，而外源性fractalkine共同给药可消除这些作用。同时，小胶质细胞抑制后可缓解外源性fractalkine诱发的急性疼痛。此外，脊髓中fractalkine/CX3CR1信号的中和减轻了胫骨骨折后术后痛觉过敏的强度。这些关键发现表明，光甘草定治疗通过抑制fractalkine/CX3CR1依赖性脊髓小胶质细胞增生和脊柱形态发生，对诱导和维持骨折引起的慢性痛觉过敏具有保护作用，这表明光甘草定是慢性骨折疼痛控制转化研究中有前景的候选药物。
