Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.
Neurotherapeutics. 2020 Jul;17(3):886-899. doi: 10.1007/s13311-020-00892-9.
The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.
当前阿片类药物滥用和慢性疼痛的危机要求开发非阿片类和非药物治疗方法来缓解疼痛。基于神经调节的方法，如脊髓刺激、背根神经节模拟和神经刺激，包括迷走神经刺激，在临床前和临床研究中已显示出控制疼痛的疗效。然而，神经调节缓解疼痛的机制尚不完全清楚。越来越多的证据表明，神经调节通过神经-免疫相互作用调节炎症和神经炎症-外周神经、背根神经节/三叉神经节和脊髓/大脑中的局部炎症。专门的促解决介质（SPM），如 resolvins、protectins、maresins 和 lipoxins 是在炎症消退阶段产生的脂类分子，在各种动物模型中具有多种缓解炎症的有益作用。最近的研究表明，SPM 通过免疫、神经胶质和神经元调节抑制炎性疼痛、术后疼痛、神经性疼痛和癌症疼痛。值得注意的是，假手术足以提高 resolvin 水平，可作为解决模型。有趣的是，已经表明迷走神经产生 SPM，迷走神经刺激（VNS）在体外诱导 SPM 的产生。在这篇综述中，我们讨论了神经调节（如 VNS）如何通过免疫调节和神经-免疫相互作用来控制疼痛，并强调了 SPM 的可能参与。特别是，我们证明了通过耳电针的 VNS 有效减轻化疗引起的神经性疼痛。此外，耳刺激能够增加小鼠体内 resolvin 的水平。因此，我们提出神经调节可能通过 SPM 控制疼痛和炎症/神经炎症。最后，我们讨论了在理解基于神经调节的治疗如何提供短期和长期疼痛缓解方面仍然存在的关键问题。
