Advertisement

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

  • Ming Tatt Lee
    Affiliations
    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
    Search for articles by this author
  • Yi-Hung Chen
    Affiliations
    Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan

    Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
    Search for articles by this author
  • Ken Mackie
    Affiliations
    Gill Center for Biomolecular Research, Indiana University, Bloomington, Indiana

    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
    Search for articles by this author
  • Lih-Chu Chiou
    Correspondence
    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.
    Affiliations
    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
    Search for articles by this author
Published:October 15, 2020DOI:https://doi.org/10.1016/j.jpain.2020.09.003

      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

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abbasi J
        Robert Kerns, PhD: Researching nondrug approaches to pain management.
        JAMA. 2018; 319: 1535-1537
        • Banks GP
        • Winfree CJ
        Evolving techniques and indications in peripheral nerve stimulation for pain.
        Neurosurg Clin N Am. 2019; 30: 265-273
        • Campbell JN
        • Long DM
        Peripheral nerve stimulation in the treatment of intractable pain.
        J Neurosurg. 1976; 45: 692-699
        • Charkhkar H
        • Christie BP
        • Pinault GJ
        • Tyler DJ
        • Triolo RJ
        A translational framework for peripheral nerve stimulating electrodes: Reviewing the journey from concept to clinic.
        J Neurosci Methods. 2019; 328108414
        • Chen EY
        • Marcantonio A
        • Tornetta 3rd, P
        Correlation between 24-hour predischarge opioid use and amount of opioids prescribed at hospital discharge.
        JAMA Surg. 2018; 153e174859
        • Chen YH
        • Lee HJ
        • Lee MT
        • Wu YT
        • Lee YH
        • Hwang LL
        • Hung MS
        • Zimmer A
        • Mackie K
        • Chiou LC
        Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray.
        Proc Natl Acad Sci U S A. 2018; 115: E10720-E10729
        • Colvin LA
        • Bull F
        • Hales TG
        Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia.
        Lancet. 2019; 393: 1558-1568
        • Crowe MS
        • Wilson CD
        • Leishman E
        • Prather PL
        • Bradshaw HB
        • Banks ML
        • Kinsey SG
        The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice.
        Br J Pharmacol. 2017; 174: 4523-4539
        • Dalal S
        • Bruera E
        Pain management for patients with advanced cancer in the opioid epidemic era.
        Am Soc Clin Oncol Educ Book. 2019; 39: 24-35
        • Deng L
        • Guindon J
        • Cornett BL
        • Makriyannis A
        • Mackie K
        • Hohmann AG
        Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal.
        Biol Psychiatry. 2015; 77: 475-487
        • Di Marzo V
        New approaches and challenges to targeting the endocannabinoid system.
        Nat Rev Drug Discov. 2018; 17: 623-639
        • Dosenovic S
        • Jelicic Kadic A
        • Miljanovic M
        • Biocic M
        • Boric K
        • Cavar M
        • Markovina N
        • Vucic K
        • Puljak L
        Interventions for neuropathic pain: An overview of systematic reviews.
        Anesth Analg. 2017; 125: 643-652
        • Dzierzanowski T
        Prospects for the use of cannabinoids in oncology and palliative care practice: A review of the evidence.
        Cancers (Basel). 2019; 11: 129
        • Eisenberg E
        • Waisbrod H
        • Gerbershagen HU
        Long-term peripheral nerve stimulation for painful nerve injuries.
        Clin J Pain. 2004; 20: 143-146
        • Fu LW
        • Longhurst JC
        Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB1 receptors.
        J Appl Physiol (1985). 2009; 106: 1800-1809
        • Gabriel RA
        • Swisher MW
        • Ilfeld BM
        Percutaneous peripheral nerve stimulation for acute postoperative pain.
        Pain Manag. 2019; 9: 347-354
        • Georgescu D
        • Zachariou V
        • Barrot M
        • Mieda M
        • Willie JT
        • Eisch AJ
        • Yanagisawa M
        • Nestler EJ
        • DiLeone RJ
        Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal.
        J Neurosci. 2003; 23: 3106-3111
        • Glare P
        • Aubrey KR
        • Myles PS
        Transition from acute to chronic pain after surgery.
        Lancet. 2019; 393: 1537-1546
        • Goldman N
        • Chen M
        • Fujita T
        • Xu Q
        • Peng W
        • Liu W
        • Jensen TK
        • Pei Y
        • Wang F
        • Han X
        • Chen JF
        • Schnermann J
        • Takano T
        • Bekar L
        • Tieu K
        • Nedergaard M
        Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture.
        Nat Neurosci. 2010; 13: 883-888
        • Gonzalez S
        • Cebeira M
        • Fernandez-Ruiz J
        Cannabinoid tolerance and dependence: A review of studies in laboratory animals.
        Pharmacol Biochem Behav. 2005; 81: 300-318
        • Hah JM
        • Bateman BT
        • Ratliff J
        • Curtin C
        • Sun E
        Chronic opioid use after surgery: Implications for perioperative management in the face of the opioid epidemic.
        Anesth Analg. 2017; 125: 1733-1740
        • Hah JM
        • Sturgeon JA
        • Zocca J
        • Sharifzadeh Y
        • Mackey SC
        Factors associated with prescription opioid misuse in a cross-sectional cohort of patients with chronic non-cancer pain.
        J Pain Res. 2017; 10: 979-987
        • Higgins C
        • Smith BH
        • Matthews K
        Incidence of iatrogenic opioid dependence or abuse in patients with pain who were exposed to opioid analgesic therapy: a systematic review and meta-analysis.
        Br J Anaesth. 2018; 120: 1335-1344
        • Ho YC
        • Lee HJ
        • Tung LW
        • Liao YY
        • Fu SY
        • Teng SF
        • Liao HT
        • Mackie K
        • Chiou LC
        Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition.
        J Neurosci. 2011; 31: 14600-14610
        • Humphreys K
        • Saitz R
        Should physicians recommend replacing opioids with cannabis?.
        JAMA. 2019; 321: 639-640
        • Jayamanne A
        • Greenwood R
        • Mitchell VA
        • Aslan S
        • Piomelli D
        • Vaughan CW
        Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models.
        Br J Pharmacol. 2006; 147: 281-288
        • Johal H
        • Devji T
        • Chang Y
        • Simone J
        • Vannabouathong C
        • Bhandari M
        Cannabinoids in chronic non-cancer pain: A systematic review and meta-analysis.
        Clin Med Insights Arthritis Musculoskelet Disord. 2020; 131179544120906461
        • Kaur R
        • Sidhu P
        • Singh S
        What failed BIA 10-2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials.
        J Pharmacol Pharmacother. 2016; 7: 120-126
        • Lee HJ
        • Chang LY
        • Ho YC
        • Teng SF
        • Hwang LL
        • Mackie K
        • Chiou LC
        Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray.
        Neuropharmacology. 2016; 105: 577-586
        • Levy RM
        Neuromodulation: The "Not-so-Hidden" cure for the opioid crisis.
        Neuromodulation. 2017; 20: 519-524
        • Lewis JW
        • Sherman JE
        • Liebeskind JC
        Opioid and non-opioid stress analgesia: assessment of tolerance and cross-tolerance with morphine.
        J Neurosci. 1981; 1: 358-363
        • Mayer DJ
        • Hayes RL
        Stimulation-produced analgesia: development of tolerance and cross-tolerance to morphine.
        Science. 1975; 188: 941-943
        • Mercadante S
        • Arcuri E
        • Santoni A
        Opioid-induced tolerance and hyperalgesia.
        CNS Drugs. 2019; 33: 943-955
        • Ming-Tatt L
        • Khalivulla SI
        • Akhtar MN
        • Lajis N
        • Perimal EK
        • Akira A
        • Ali DI
        • Sulaiman MR
        Anti-hyperalgesic effect of a benzilidine-cyclohexanone analogue on a mouse model of chronic constriction injury-induced neuropathic pain: Participation of the kappa-opioid receptor and KATP.
        Pharmacol Biochem Behav. 2013; 114-115: 58-63
        • Mirone G
        • Natale M
        • Rotondo M
        Peripheral median nerve stimulation for the treatment of iatrogenic complex regional pain syndrome (CRPS) type II after carpal tunnel surgery.
        J Clin Neurosci. 2009; 16: 825-827
        • Mobbs RJ
        • Nair S
        • Blum P
        Peripheral nerve stimulation for the treatment of chronic pain.
        J Clin Neurosci. 2007; 14 (discussion 222-213): 216-221
        • Morgan DJ
        • Davis BJ
        • Kearn CS
        • Marcus D
        • Cook AJ
        • Wager-Miller J
        • Straiker A
        • Myoga MH
        • Karduck J
        • Leishman E
        • Sim-Selley LJ
        • Czyzyk TA
        • Bradshaw HB
        • Selley DE
        • Mackie K
        Mutation of putative GRK phosphorylation sites in the cannabinoid receptor 1 (CB1R) confers resistance to cannabinoid tolerance and hypersensitivity to cannabinoids in mice.
        J Neurosci. 2014; 34: 5152-5163
        • Morgan MM
        • Christie MJ
        Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human.
        Br J Pharmacol. 2011; 164: 1322-1334
        • Nashold Jr., BS
        • Goldner JL
        • Mullen JB
        • Bright DS
        Long-term pain control by direct peripheral-nerve stimulation.
        J Bone Joint Surg Am. 1982; 64: 1-10
        • Neuman MD
        • Bateman BT
        • Wunsch H
        Inappropriate opioid prescription after surgery.
        Lancet. 2019; 393: 1547-1557
        • Nielsen S
        • Sabioni P
        • Trigo JM
        • Ware MA
        • Betz-Stablein BD
        • Murnion B
        • Lintzeris N
        • Khor KE
        • Farrell M
        • Smith A
        • Le Foll B
        Opioid-sparing effect of cannabinoids: A systematic review and meta-analysis.
        Neuropsychopharmacology. 2017; 42: 1752-1765
        • Okine BN
        • Norris LM
        • Woodhams S
        • Burston J
        • Patel A
        • Alexander SP
        • Barrett DA
        • Kendall DA
        • Bennett AJ
        • Chapman V
        Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: Evidence for plastic changes in the endocannabinoid system.
        Br J Pharmacol. 2012; 167: 627-640
        • Osikowicz M
        • Mika J
        • Makuch W
        • Przewlocka B
        Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain.
        Pain. 2008; 139: 117-126
        • Pahwa R
        • Dhall R
        • Ostrem J
        • Gwinn R
        • Lyons K
        • Ro S
        • Dietiker C
        • Luthra N
        • Chidester P
        • Hamner S
        • Ross E
        • Delp S
        An acute randomized controlled trial of noninvasive peripheral nerve stimulation in essential tremor.
        Neuromodulation. 2019; 22: 537-545
        • Petrosino S
        • Palazzo E
        • de Novellis V
        • Bisogno T
        • Rossi F
        • Maione S
        • Di Marzo V
        Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats.
        Neuropharmacology. 2007; 52: 415-422
        • Quintero GC
        Review about gabapentin misuse, interactions, contraindications and side effects.
        J Exp Pharmacol. 2017; 9: 13-21
        • Rabgay K
        • Waranuch N
        • Chaiyakunapruk N
        • Sawangjit R
        • Ingkaninan K
        • Dilokthornsakul P
        The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis.
        J Am Pharm Assoc (2003). 2020; 60 (e226): 225-234
        • Russo EB
        Cannabinoids in the management of difficult to treat pain.
        Ther Clin Risk Manag. 2008; 4: 245-259
        • Russo R
        • Loverme J
        • La Rana G
        • Compton TR
        • Parrott J
        • Duranti A
        • Tontini A
        • Mor M
        • Tarzia G
        • Calignano A
        • Piomelli D
        The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice.
        J Pharmacol Exp Ther. 2007; 322: 236-242
        • Schneiderhan J
        • Clauw D
        • Schwenk TL
        Primary care of patients with chronic pain.
        JAMA. 2017; 317: 2367-2368
        • Skolnick P
        The opioid epidemic: Crisis and solutions.
        Annu Rev Pharmacol Toxicol. 2018; 58: 143-159
        • Slavin KV
        Technical aspects of peripheral nerve stimulation: Hardware and complications.
        Prog Neurol Surg. 2011; 24: 189-202
        • Smith RV
        • Havens JR
        • Walsh SL
        Gabapentin misuse, abuse and diversion: A systematic review.
        Addiction. 2016; 111: 1160-1174
        • Stockings E
        • Campbell G
        • Hall WD
        • Nielsen S
        • Zagic D
        • Rahman R
        • Murnion B
        • Farrell M
        • Weier M
        • Degenhardt L
        Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: A systematic review and meta-analysis of controlled and observational studies.
        Pain. 2018; 159: 1932-1954
        • Suplita 2nd, RL
        • Eisenstein SA
        • Neely MH
        • Moise AM
        • Hohmann AG
        Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia.
        Neuropharmacology. 2008; 54: 161-171
        • Thannickal TC
        • John J
        • Shan L
        • Swaab DF
        • Wu MF
        • Ramanathan L
        • McGregor R
        • Chew KT
        • Cornford M
        • Yamanaka A
        • Inutsuka A
        • Fronczek R
        • Lammers GJ
        • Worley PF
        • Siegel JM
        Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy.
        Sci Transl Med. 2018; 10
        • Tjen ALSC
        • Li P
        • Longhurst JC
        Processing cardiovascular information in the vlPAG during electroacupuncture in rats: Roles of endocannabinoids and GABA.
        J Appl Physiol (1985). 2009; 106: 1793-1799
        • US-FDA
        Administration, U.S.F.a.D. StimQ Peripheral Nerve Stimulator (PNS) System 510(k) Premarket Notification. 2016
        • US-FDA
        Administration, U.S.F.a.D. External Upper Limb Tremor Stimulator 510(k) Premarket Notification. 2018 (Silver Spring, MD)
        • US-FDA
        Administration, U.S.F.a.D. SPRINT Peripheral Nerve Stimulation System, Extensa, SPRINT Peripheral Nerve Stimulation System, Endura, SPRINT Clinical Programmer Kit 510(k) Premarket Notification. 2018
      1. US-FDA: FDA permits marketing of first medical device for relief of pain associated with irritable bowel syndrome in patients 11-18 years of age, 2019.

        • Van Calenbergh F
        • Gybels J
        • Van Laere K
        • Dupont P
        • Plaghki L
        • Depreitere B
        • Kupers R
        Long term clinical outcome of peripheral nerve stimulation in patients with chronic peripheral neuropathic pain.
        Surg Neurol. 2009; 72 (discussion 335): 330-335
        • Vigano D
        • Grazia Cascio M
        • Rubino T
        • Fezza F
        • Vaccani A
        • Di Marzo V
        • Parolaro D
        Chronic morphine modulates the contents of the endocannabinoid, 2-arachidonoyl glycerol, in rat brain.
        Neuropsychopharmacology. 2003; 28: 1160-1167
        • Walker G
        The opioid crisis: A 21st century pain.
        Drugs Today (Barc). 2018; 54: 283-286
        • Walker JB
        • Katz RL
        Non-opioid pathways suppress pain in humans.
        Pain. 1981; 11: 347-354
        • Walker JB
        • Katz RL
        Peripheral nerve stimulation in the management of dysmenorrhea.
        Pain. 1981; 11: 355-361
        • Wall PD
        • Sweet WH
        Temporary abolition of pain in man.
        Science. 1967; 155: 108-109
        • Webster LR.
        Risk factors for opioid-use disorder and overdose.
        Anesth Analg. 2017; 125: 1741-1748
        • WHO
        Organization W.H. WHO Standard Acupuncture Point Locations in the Western Pacific Region. World Health Organization Western Pacific Region, Manila, Philippines2008
        • WHO
        WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents.
        WHO Guidelines Approved by the Guidelines Review Committee, Geneva2018
        • Wiffen PJ
        • Derry S
        • Bell RF
        • Rice AS
        • Tolle TR
        • Phillips T
        • Moore RA
        Gabapentin for chronic neuropathic pain in adults.
        Cochrane Database Syst Rev. 2017; 6CD007938
        • Wilkerson JL
        • Niphakis MJ
        • Grim TW
        • Mustafa MA
        • Abdullah RA
        • Poklis JL
        • Dewey WL
        • Akbarali H
        • Banks ML
        • Wise LE
        • Cravatt BF
        • Lichtman AH
        The selective monoacylglycerol lipase inhibitor MJN110 produces opioid-sparing effects in a mouse neuropathic pain model.
        J Pharmacol Exp Ther. 2016; 357: 145-156
        • Wilson-Poe AR
        • Lau BK
        • Vaughan CW
        Repeated morphine treatment alters cannabinoid modulation of GABAergic synaptic transmission within the rat periaqueductal grey.
        Br J Pharmacol. 2015; 172: 681-690
        • Wilson-Poe AR
        • Morgan MM
        • Aicher SA
        • Hegarty DM
        Distribution of CB1 cannabinoid receptors and their relationship with mu-opioid receptors in the rat periaqueductal gray.
        Neuroscience. 2012; 213: 191-200
        • Wong CS
        • Hui GK
        • Chung EK
        • Wong SH
        Diagnosis and management of neuropathic pain.
        Pain Manag. 2014; 4: 221-231
        • Woodhams SG
        • Chapman V
        • Finn DP
        • Hohmann AG
        • Neugebauer V
        The cannabinoid system and pain.
        Neuropharmacology. 2017; 124: 105-120
        • Wunsch H
        • Wijeysundera DN
        • Passarella MA
        • Neuman MD
        Opioids prescribed after low-risk surgical procedures in the United States, 2004-2012.
        JAMA. 2016; 315: 1654-1657