Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia.
Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
J Pain. 2021 Mar;22(3):300-312. doi: 10.1016/j.jpain.2020.09.003. Epub 2020 Oct 15.
Analgesic tolerance to opioids contributes to the opioid crisis by increasing the quantity of opioids prescribed and consumed. Thus, there is a need to develop non-opioid-based pain-relieving regimens as well as strategies to circumvent opioid tolerance. Previously, we revealed a non-opioid analgesic mechanism induced by median nerve electrostimulation at the overlaying PC6 (Neiguan) acupoint (MNS-PC6). Here, we further examined the efficacy of MNS-PC6 in morphine-tolerant mice with neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Daily treatments of MNS-PC6 (2 Hz, 2 mA), but not electrostimulation at a nonmedian nerve-innervated location, for a week post-CCI induction significantly suppressed established mechanical allodynia in CCI-mice in an orexin-1 (OX) and cannabinoid-1 (CB) receptor-dependent fashion. This antiallodynic effect induced by repeated MNS-PC6 was comparable to that induced by repeated gabapentin (50 mg/kg, i.p.) or single morphine (10 mg/kg, i.p.) treatments, but without tolerance, unlike repeated morphine-induced analgesia. Furthermore, single and repeated MNS-PC6 treatments remained fully effective in morphine-tolerant CCI-mice, also in an OX and CB receptor-dependent fashion. In CCI-mice receiving escalating doses of morphine for 21 days (10, 20 and 50 mg/kg), single and repeated MNS-PC6 treatments remained fully effective. Therefore, repeated MNS-PC6 treatments induce analgesia without tolerance, and retain efficacy in opioid-tolerant mice via a mechanism that involves OX and CB receptors. This study suggests that MNS-PC6 is an alternative pain management strategy that maybe useful for combatting the opioid epidemic, and opioid-tolerant patients receiving palliative care. PERSPECTIVE: Median nerve stimulation relieves neuropathic pain in mice without tolerance and retains efficacy even in mice with analgesic tolerance to escalating doses of morphine, via an opioid-independent, orexin-endocannabinoid-mediated mechanism. This study provides a proof of concept for utilizing peripheral nerve stimulating devices for pain management in opioid-tolerant patients.
电针对 PC6 穴位（内关）的刺激可产生非阿片类镇痛作用，从而缓解神经病理性疼痛，并克服阿片类药物耐受。本文在此基础上，进一步研究了电针对慢性坐骨神经结扎（CCI）诱导的痛觉过敏模型的疗效。结果显示，CCI 后第 1 天开始每天电刺激（2 Hz，2 mA）1 周可明显缓解 CCI 诱导的机械性痛觉过敏，且该作用呈阿片受体（orexin-1 和 cannabinoid-1）依赖性。这种镇痛效果与重复给予加巴喷丁（50 mg/kg，ip）或单次给予吗啡（10 mg/kg，ip）相当，但无耐受现象，而重复给予吗啡则会产生耐受。此外，在吗啡耐受的 CCI 模型中，单次和重复电刺激内关穴仍有效，同样呈阿片受体依赖性。在接受递增剂量吗啡（10、20 和 50 mg/kg）治疗 21 天的 CCI 模型中，单次和重复电刺激内关穴仍有效。综上，电针对内关穴的刺激可产生非阿片类镇痛作用，且无耐受现象，在阿片类药物耐受的模型中仍有效，其作用机制涉及阿片受体以外的 orexin-endocannabinoid 系统。该研究为利用外周神经刺激装置治疗阿片类药物耐受患者提供了理论依据。
