Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030.
Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2405465121. doi: 10.1073/pnas.2405465121. Epub 2024 Aug 15.
Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.
超过一半的脊髓损伤 (SCI) 患者会出现阿片类药物耐药性慢性神经性疼痛。加巴喷丁类药物（如普瑞巴林和加巴喷丁）是治疗神经性疼痛的阿片类药物更安全的替代品。临床上，加巴喷丁类药物似乎能增强阿片类药物的作用，增加镇痛效果和与过量相关的不良后果，但缺乏体外证明这种增强作用及其机制的证据。我们之前的研究表明，SCI 后，大鼠感觉神经元对阿片类药物的敏感性降低了 4 到 6 倍。在这里，我们证明，损伤后，加巴喷丁类药物恢复了阿片类药物抑制环腺苷酸 (cAMP) 生成的正常敏感性，同时通过抑制电压门控钙通道 (VGCCs) 抑制伤害感受器的过度兴奋。通过增加细胞内 Ca2+或激活 L 型 VGCCs（L-VGCCs），足以模拟 SCI 对阿片类药物敏感性的影响，这种方式依赖于 Raf1 原癌基因丝氨酸/苏氨酸蛋白激酶 C-Raf 的活性，但与神经元去极化无关。总之，我们的研究结果提供了一种机制，即损伤后加巴喷丁类药物通过减少 L-VGCC 内流增强阿片类药物的作用，并表明其他靶向这些通道的抑制剂可能同样增强阿片类药物治疗神经性疼痛的效果。
