Highlights
- •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.
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.
Key Words
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Article info
Publication history
Published online: October 15, 2020
Accepted:
September 25,
2020
Received in revised form:
September 23,
2020
Received:
June 11,
2020
Footnotes
Research funding: This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST104-2745-B-002-004, MOST106-2321-B-002-019, MOST107-2321-B-002-010, MOST 108-2321-B-002-005, MOST 108-2320-B-002-029-MY3 and 109-2320-B-002-042-MY3 to L.-C.C.), National Health Research Institutes, Taiwan (NHRI-EX109-10733NI to L.-C.C.), Ministry of Education, Taiwan (107M4022-3 to L.-C.C.) and National Institute of Health, USA (DA041229 and DA047858 to K.M.).
Conflicts of interest statement: The authors declare no conflicts of interest.
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© 2020 by United States Association for the Study of Pain, Inc.
