Involvement of Opioid Receptors and α2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study

  • Lechi Vo
    Centre for Research on Chronic Pain and Inflammatory Diseases, and School of Psychology and Exercise Science, Murdoch University, Perth, Western Australia, Australia
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  • Sean Hood
    School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia
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  • Peter D. Drummond
    Address reprint requests to Professor Peter D. Drummond, PhD, School of Psychology and Exercise Science, Murdoch University, Perth, WA 6150, Australia.
    Centre for Research on Chronic Pain and Inflammatory Diseases, and School of Psychology and Exercise Science, Murdoch University, Perth, Western Australia, Australia
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Published:August 04, 2016DOI:


      • Limb pain evokes an ipsilateral form of conditioned pain modulation.
      • Opioid peptides mediate this response in the painful limb and ipsilateral forehead.
      • These inhibitory opioid influences override opposing α2-adrenoceptor effects.
      • Failure of this ipsilateral opioid response may aggravate chronic limb or head pain.


      In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only evokes local signs of central sensitization but also triggers broader ipsilateral inhibitory influences on pain akin to a lateralized form of conditioned pain modulation. Paradoxically, some of these inhibitory influences are augmented by α2-adrenoceptor blockade. To determine whether opioid peptides mediate inhibitory effects after HFS, the opioid receptor antagonist naltrexone was coadministered orally with the α2-adrenoceptor antagonist yohimbine in 16 healthy women in a double-blind placebo-controlled crossover study. In each session, mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, pain ratings to electrical stimulation of HFS-treated or control sites in the forearm were assessed during and after painful stimulation of each temple. Unlike yohimbine alone, the naltrexone with yohimbine combination blocked analgesia evoked by HFS in the ipsilateral forehead to blunt pressure, and opposed the ipsilateral inhibitory effect of pain in the temple on electrically-evoked pain at the HFS-treated site in the forearm. These findings imply involvement of opioid peptides in an ipsilateral analgesic response that complements the more generalized form of conditioned pain modulation. Opioid mediation of this ipsilateral analgesic response appears to override opposing α2-adrenoceptor effects.


      HFS not only evokes local signs of central sensitization but also triggers a broader ipsilateral antinociceptive mechanism mediated by opioid receptors. Dysfunction of this lateralized pain modulation process might contribute to painful unilateral disorders such as migraine or complex regional pain syndrome.

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        • Bajic D.
        • Proudfit H.K.
        Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception.
        J Comp Neurol. 1999; 405: 359-379
        • Bannister K.
        • Patel R.
        • Goncalves L.
        • Townson L.
        • Dickenson A.H.
        Diffuse noxious inhibitory controls and nerve injury: Restoring an imbalance between descending monoamine inhibitions and facilitations.
        Pain. 2015; 156: 1803-1811
        • Bharucha A.E.
        • Camilleri M.
        • Zinsmeister A.R.
        • Hanson R.B.
        Adrenergic modulation of human colonic motor and sensory function.
        Am J Physiol. 1997; 273: G997-G1006
        • Bruehl S.
        • Chung O.Y.
        • Diedrich L.
        • Diedrich A.
        • Robertson D.
        The relationship between resting blood pressure and acute pain sensitivity: Effects of chronic pain and alpha-2 adrenergic blockade.
        J Behav Med. 2008; 31: 71-80
        • Burstein R.
        • Cutrer M.F.
        • Yarnitsky D.
        The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine.
        Brain. 2000; 123: 1703-1709
        • Chabot-Dore A.J.
        • Schuster D.J.
        • Stone L.S.
        • Wilcox G.L.
        Analgesic synergy between opioid and alpha2 -adrenoceptors.
        Br J Pharmacology. 2015; 172: 388-402
        • Chung O.Y.
        • Bruehl S.
        • Diedrich L.
        • Diedrich A.
        The impact of blood pressure and baroreflex sensitivity on wind-up.
        Anesth Analg. 2008; 107: 1018-1025
        • Drummond P.D.
        • Finch P.M.
        Sensory changes in the forehead of patients with complex regional pain syndrome.
        Pain. 2006; 123: 83-89
        • Frew A.K.
        • Drummond P.D.
        Negative affect, pain and sex: The role of endogenous opioids.
        Pain. 2007; 132: S77-S85
        • Frew A.K.
        • Drummond P.D.
        Stress-evoked opioid release inhibits pain in major depressive disorder.
        Pain. 2008; 139: 284-292
        • Frew A.K.
        • Drummond P.D.
        Opposite effects of opioid blockade on the blood pressure-pain relationship in depressed and non-depressed participants.
        Pain. 2009; 142: 68-74
        • Gear R.W.
        • Gordon N.C.
        • Heller P.H.
        • Levine J.D.
        Enhancement of morphine analgesia by the alpha 2-adrenergic antagonist yohimbine.
        Neuroscience. 1995; 66: 5-8
        • Gjerstad J.
        • Tjolsen A.
        • Svendsen F.
        • Hole K.
        Inhibition of spinal nociceptive responses after intramuscular injection of capsaicin involves activation of noradrenergic and opioid systems.
        Brain Res. 2000; 859: 132-136
        • Goldberg M.R.
        • Robertson D.
        Yohimbine: A pharmacological probe for study of the alpha 2-adrenoreceptor.
        Pharmacol Rev. 1983; 35: 143-180
        • Gonzalez J.P.
        • Brogden R.N.
        Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence.
        Drugs. 1988; 35: 192-213
        • Huang H.P.
        • Zhu F.P.
        • Chen X.W.
        • Xu Z.Q.
        • Zhang C.X.
        • Zhou Z.
        Physiology of quantal norepinephrine release from somatodendritic sites of neurons in locus coeruleus.
        Front Mol Neurosci. 2012; 5: 29
        • Jeong Y.
        • Holden J.E.
        Lateral hypothalamic-induced alpha-adrenoceptor modulation occurs in a model of inflammatory pain in rats.
        Biol Res Nurs. 2009; 10: 331-339
        • King C.D.
        • Goodin B.
        • Kindler L.L.
        • Caudle R.M.
        • Edwards R.R.
        • Gravenstein N.
        • Riley 3rd, J.L.
        • Fillingim R.B.
        Reduction of conditioned pain modulation in humans by naltrexone: An exploratory study of the effects of pain catastrophizing.
        J Behav Med. 2013; 36: 315-327
        • Klein T.
        • Magerl W.
        • Hopf H.C.
        • Sandkuhler J.
        • Treede R.D.
        Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.
        J Neurosci. 2004; 24: 964-971
        • Klein T.
        • Stahn S.
        • Magerl W.
        • Treede R.D.
        The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation.
        Pain. 2008; 139: 507-519
        • Knudsen L.
        • Drummond P.D.
        Cold-induced limb pain decreases sensitivity to pressure-pain sensations in the ipsilateral forehead.
        Eur J Pain. 2009; 13: 1023-1029
        • Knudsen L.
        • Drummond P.D.
        Cutaneous limb inflammation produces analgesia to pressure pain in the ipsilateral forehead of healthy volunteers.
        J Pain. 2011; 12: 451-459
        • Knudsen L.
        • Finch P.M.
        • Drummond P.D.
        The specificity and mechanisms of hemilateral sensory disturbances in complex regional pain syndrome.
        J Pain. 2011; 12: 985-990
        • Kwiat G.C.
        • Basbaum A.I.
        The origin of brainstem noradrenergic and serotonergic projections to the spinal cord dorsal horn in the rat.
        Somatosens Mot Res. 1992; 9: 157-173
        • Lang S.
        • Klein T.
        • Magerl W.
        • Treede R.D.
        Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways.
        Pain. 2007; 128: 254-263
        • Liu N.
        • Bonnet F.
        • Delaunay L.
        • Kermarec N.
        • D’Honneur G.
        Partial reversal of the effects of extradural clonidine by oral yohimbine in postoperative patients.
        Br J Anaesthesia. 1993; 70: 515-518
        • Luttinger D.
        • Ferrari R.
        • Perrone M.H.
        • Haubrich D.R.
        Pharmacological analysis of alpha-2 adrenergic mechanisms in nociception and ataxia.
        J Pharmacol Exp Ther. 1985; 232: 883-889
        • Malcolm A.
        • Camilleri M.
        • Kost L.
        • Burton D.D.
        • Fett S.L.
        • Zinsmeister A.R.
        Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function.
        Aliment Pharmacol Ther. 2000; 14: 783-793
        • Malcolm A.
        • Phillips S.F.
        • Camilleri M.
        • Hanson R.B.
        Pharmacological modulation of rectal tone alters perception of distention in humans.
        Am J Gastroenterol. 1997; 92: 2073-2079
        • Martini C.
        • van Velzen M.
        • Drewes A.
        • Aarts L.
        • Dahan A.
        • Niesters M.
        A randomized controlled trial on the effect of tapentadol and morphine on conditioned pain modulation in healthy volunteers.
        PLoS One. 2015; 10: e0128997
        • McCubbin J.A.
        • Bruehl S.
        • Wilson J.F.
        • Sherman J.J.
        • Norton J.A.
        • Colclough G.
        Endogenous opioids inhibit ambulatory blood pressure during naturally occurring stress.
        Psychosom Med. 1998; 60: 227-231
        • Millan M.J.
        Descending control of pain.
        Prog Neurobiol. 2002; 66: 355-474
        • Nuseir K.
        • Proudfit H.K.
        Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons.
        Neuroscience. 2000; 96: 773-783
        • Pan H.L.
        • Wu Z.Z.
        • Zhou H.Y.
        • Chen S.R.
        • Zhang H.M.
        • Li D.P.
        Modulation of pain transmission by G-protein-coupled receptors.
        Pharmacol Ther. 2008; 117: 141-161
        • Pertovaara A.
        • Kemppainen P.
        • Johansson G.
        • Karonen S.L.
        Ischemic pain nonsegmentally produces a predominant reduction of pain and thermal sensitivity in man: A selective role for endogenous opioids.
        Brain Res. 1982; 251: 83-92
        • Pfau D.B.
        • Klein T.
        • Putzer D.
        • Pogatzki-Zahn E.M.
        • Treede R.D.
        • Magerl W.
        Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity.
        Pain. 2011; 152: 1532-1539
        • Sadeghi M.
        • Tzschentke T.M.
        • Christie M.J.
        μ-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons.
        Br J Pharmacol. 2015; 172: 460-468
        • Sprenger C.
        • Bingel U.
        • Buchel C.
        Treating pain with pain: Supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation.
        Pain. 2011; 152: 428-439
        • Tam S.W.
        • Worcel M.
        • Wyllie M.
        Yohimbine: A clinical review.
        Pharmacol Ther. 2001; 91: 215-243
        • Tsuruoka M.
        • Hiruma Y.
        • Matsutani K.
        • Matsui Y.
        Effects of yohimbine on naloxone-induced antinociception in a rat model of inflammatory hyperalgesia.
        Eur J Pharmacol. 1998; 348: 161-165
        • Tsuruoka M.
        • Hitoto T.
        • Hiruma Y.
        • Matsui Y.
        Neurochemical evidence for inflammation-induced activation of the coeruleospinal modulation system in the rat.
        Brain Res. 1999; 821: 236-240
        • Tsuruoka M.
        • Maeda M.
        • Inoue T.
        Persistent hindpaw inflammation produces coeruleospinal antinociception in the non-inflamed forepaw of rats.
        Neurosci Lett. 2004; 367: 66-70
        • Tsuruoka M.
        • Matsutani K.
        • Inoue T.
        Coeruleospinal inhibition of nociceptive processing in the dorsal horn during unilateral hindpaw inflammation in the rat.
        Pain. 2003; 104: 353-361
        • Tzschentke T.M.
        • Christoph T.
        • Kogel B.Y.
        The mu-opioid receptor agonist/noradrenaline reuptake inhibition (MOR-NRI) concept in analgesia: The case of tapentadol.
        CNS Drugs. 2014; 28: 319-329
        • Van Bockstaele E.J.
        • Reyes B.A.
        • Valentino R.J.
        The locus coeruleus: A key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse.
        Brain Res. 2010; 1314: 162-174
        • van den Broeke E.N.
        • Mouraux A.
        High-frequency electrical stimulation of the human skin induces heterotopical mechanical hyperalgesia, heat hyperalgesia, and enhanced responses to nonnociceptive vibrotactile input.
        J Neurophysiol. 2014; 111: 1564-1573
        • Villanueva L.
        • Bouhassira D.
        • Le Bars D.
        The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals.
        Pain. 1996; 67: 231-240
        • Vo L.
        • Drummond P.D.
        High frequency electrical stimulation concurrently induces central sensitization and ipsilateral inhibitory pain modulation.
        Eur J Pain. 2013; 17: 357-368
        • Vo L.
        • Drummond P.D.
        Analgesia to pressure-pain develops in the ipsilateral forehead after high- and low-frequency electrical stimulation of the forearm.
        Exp Brain Res. 2014; 232: 685-693
        • Vo L.
        • Drummond P.D.
        Coexistence of ipsilateral pain-inhibitory and facilitatory processes after high-frequency electrical stimulation.
        Eur J Pain. 2014; 18: 376-385
        • Vo L.
        • Drummond P.D.
        Involvement of alpha-adrenoceptors in inhibitory and facilitatory pain modulation processes.
        Eur J Pain. 2016; 20: 386-398
        • Wei H.
        • Pertovaara A.
        Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat.
        Eur J Pharmacol. 2006; 551: 41-49
        • Wen Y.R.
        • Wang C.C.
        • Yeh G.C.
        • Hsu S.F.
        • Huang Y.J.
        • Li Y.L.
        • Sun W.Z.
        DNIC-mediated analgesia produced by a supramaximal electrical or a high-dose formalin conditioning stimulus: roles of opioid and alpha2-adrenergic receptors.
        J Biomed Sci. 2010; 17: 19
        • Willer J.C.
        • Le Bars D.
        • De Broucker T.
        Diffuse noxious inhibitory controls in man: involvement of an opioidergic link.
        Eur J Pharmacol. 1990; 182: 347-355
        • Yarnitsky D.
        Role of endogenous pain modulation in chronic pain mechanisms and treatment.
        Pain. 2015; 156: S24-S31