Median Nerve Stimulation as a Nonpharmacological Approach to Bypass Analgesic Tolerance to Morphine: A Proof-of-Concept Study in Mice

  • Ming Tatt Lee
    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
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  • Yi-Hung Chen
    Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan

    Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
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  • Ken Mackie
    Gill Center for Biomolecular Research, Indiana University, Bloomington, Indiana

    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
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  • Lih-Chu Chiou
    Address reprint requests to Lih-Chu Chiou, PhD, Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei 100 Taiwan.
    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

    Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan
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Published:October 15, 2020DOI:


      • Repeated median nerve stimulation-induced analgesia is opioid-independent.
      • Orexin-initiated endocannabinoid signaling, possibly in the PAG, mediates MNS-IA.
      • Unlike opioids or cannabinoids, tolerance doesn't develop to repeated MNS-IA in neuropathic mice.
      • Repeated MNS-IA is effective in mice tolerant to escalating doses of morphine.
      • Peripheral neuromodulation has pain management potential in opioid-tolerant patients.


      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 (OX1) and cannabinoid-1 (CB1) 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 OX1 and CB1 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 OX1 and CB1 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.


      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.

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