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

  • Lechi Vo
    Affiliations
    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
    Affiliations
    School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia
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  • Peter D. Drummond
    Correspondence
    Address reprint requests to Professor Peter D. Drummond, PhD, School of Psychology and Exercise Science, Murdoch University, Perth, WA 6150, Australia.
    Affiliations
    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:https://doi.org/10.1016/j.jpain.2016.07.004

      Highlights

      • 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.

      Abstract

      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.

      Perspective

      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.

      Key words

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