Affiliations 

  • 1 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
  • 2 Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
  • 3 Gill Center for Biomolecular Research, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
  • 4 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. Electronic address: lcchiou@ntu.edu.tw
J Pain, 2021 03;22(3):300-312.
PMID: 33069869 DOI: 10.1016/j.jpain.2020.09.003

Abstract

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. 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.