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The Delta-Opioid Receptor Bidirectionally Modulates Itch

  • Author Footnotes
    2 K.M.S and E.N. are co-first authors.
    Kelly M. Smith
    Footnotes
    2 K.M.S and E.N. are co-first authors.
    Affiliations
    University of Pittsburgh School of Medicine, Department of Neurobiology,Pittsburgh, Pennsylvania

    University of Pittsburgh, Pittsburgh Center for Pain Research, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Author Footnotes
    2 K.M.S and E.N. are co-first authors.
    Eileen Nguyen
    Footnotes
    2 K.M.S and E.N. are co-first authors.
    Affiliations
    University of Pittsburgh School of Medicine, Department of Neurobiology,Pittsburgh, Pennsylvania

    University of Pittsburgh, Pittsburgh Center for Pain Research, Pittsburgh, Pennsylvania

    University of Pittsburgh School of Medicine, Medical Scientist Training Program, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Sarah E. Ross
    Correspondence
    Address reprint requests to Sarah E. Ross, PhD, 200 Lothrop St, Pittsburgh, 15213 PA
    Affiliations
    University of Pittsburgh School of Medicine, Department of Neurobiology,Pittsburgh, Pennsylvania

    University of Pittsburgh, Pittsburgh Center for Pain Research, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Author Footnotes
    2 K.M.S and E.N. are co-first authors.
Published:November 30, 2022DOI:https://doi.org/10.1016/j.jpain.2022.09.013

      Highlights

      • Delta- Opioid Receptor(DOR) in the spinal dorsal horn bidirectionally modulates itch
      • The endogenous ligand for DOR, enkephalin, is expressed on spinal neurons that co-express neuropeptide Y (NPY)
      • Spinal neurons that express DOR co-express NPY1R and Kappa-opioid Receptor(KOR).
      • Neurons that co-express the DOR and KOR are activated following peripheral chloroquine injection

      Abstract

      Opioid signaling has been shown to be critically important in the neuromodulation of sensory circuits in the superficial spinal cord. Agonists of the mu-opioid receptor (MOR) elicit itch, whereas agonists of the kappa-opioid receptor (KOR) have been shown to inhibit itch. Despite the clear roles of MOR and KOR for the modulation itch, whether the delta-opioid receptor (DOR) is involved in the regulation of itch remained unknown. Here, we show that intrathecal administration of DOR agonists suppresses chemical itch and that intrathecal application of DOR antagonists is sufficient to evoke itch. We identify that spinal enkephalin neurons co-express neuropeptide Y (NPY), a peptide previously implicated in the inhibition of itch. In the spinal cord, DOR overlapped with both the NPY receptor (NPY1R) and KOR, suggesting that DOR neurons represent a site for convergent itch information in the dorsal horn. Lastly, we found that neurons co-expressing DOR and KOR showed significant Fos induction following pruritogen-evoked itch. These results uncover a role for DOR in the modulation of itch in the superficial dorsal horn.
      Perspective: This article reveals the role of the delta-opioid receptor in itch. Intrathecal administration of delta agonists suppresses itch whereas the administration of delta antagonists is sufficient to induce itch. These studies highlight the importance of delta-opioid signaling for the modulation of itch behaviors, which may represent new targets for the management of itch disorders.

      Keywords

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