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需要开发非阿片类药物和非药物疗法来缓解疼痛。基于神经调节的方法，例如脊髓刺激、背根神经节模拟和包括迷走神经刺激在内的神经刺激，已在临床前和临床研究中显示出在实现疼痛控制方面的功效。然而，神经调节减轻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来调节炎症和神经炎症——周围神经、背根神经节/三叉神经节和脊髓/大脑的局部炎症。专门的促消退介质 (SPM)，例如消退素、保护素、maresins 和脂氧素，是炎症消退阶段产生的脂质分子，在各种动物模型中在消退炎症方面表现出多种有益作用。最近的研究表明，SPM 通过免疫、神经胶质和神经元调节来抑制啮齿动物模型中的炎性疼痛、术后疼痛、神经性疼痛和癌症疼痛。值得注意的是，假手术足以提高消退素水平，并且可以作为消退的模型。有趣的是，研究表明迷走神经会产生 SPM，而迷走神经刺激 (VNS) 会在体外诱导 SPM 的产生。在这篇综述中，我们讨论了 VNS 等神经调节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 可能的参与。特别是，我们证明通过耳穴电针进行迷走神经刺激可以有效减轻化疗引起的神经性疼痛。此外，耳部刺激能够增加小鼠的消退素水平。 因此，我们提出神经调节可以通过 SPM 控制疼痛和炎症/神经炎症。最后，我们讨论了在我们对基于神经调节的疗法如何提供短期和长期疼痛缓解的理解中仍未得到解答的关键问题。