Pain Medicine  |   August 2019
Cross-talk between Human Spinal Cord μ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior
Author Notes
  • From the Center for the Study of Itch, Departments of Anesthesiology, Psychiatry and Developmental Biology (X.-Y.L., Z.-F.C.), the Division of Obstetric Anesthesiology, Department of Anesthesiology, Barnes Jewish Hospital (Y.G., A.H.), Washington University School of Medicine, St. Louis, Missouri; the Mother and Child Anesthesia Unit, Department of Anesthesiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (Y.G.); and SpineMore Surgical Associates, St. Louis, Missouri (J.Y.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • The work presented in this article has been presented at the 50th Annual Meeting of the Society of Obstetric Anesthesia and Perinatology in Miami, Florida, on May 9 to 13, 2018.
    The work presented in this article has been presented at the 50th Annual Meeting of the Society of Obstetric Anesthesia and Perinatology in Miami, Florida, on May 9 to 13, 2018.×
  • X.-Y.L. and Y.G. contributed equally to this article.
    X.-Y.L. and Y.G. contributed equally to this article.×
  • Submitted for publication August 26, 2018. Accepted for publication March 26, 2019.
    Submitted for publication August 26, 2018. Accepted for publication March 26, 2019.×
  • Address correspondence to Dr. Ginosar: Department of Anesthesiology, Hadassah Hebrew University Medical Center, Ein Karem, P.O. Box 12000 Jerusalem, Israel 91120. ginosar@wustl.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology / Opioid
Pain Medicine   |   August 2019
Cross-talk between Human Spinal Cord μ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior
Anesthesiology 8 2019, Vol.131, 381-391. doi:10.1097/ALN.0000000000002776
Anesthesiology 8 2019, Vol.131, 381-391. doi:10.1097/ALN.0000000000002776
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The spinal administration of opioids can cause intense pruritis

  • Interactions between specific μ-opioid receptor isoforms and the gastrin releasing peptide receptor in spinal tissues likely mediate morphine-induced pruritus

What This Article Tells Us That Is New:

  • Human spinal cord tissue expresses the 1Y isoform of the μ-opioid receptor, and that isoform functionally interacts with the gastrin releasing peptide receptor to cause cellular calcium influx

  • Blocking interactions between the 1Y isoform and the gastrin releasing peptide receptor does not reduce opioid analgesia

  • Eliminating interactions between the 1Y isoform and the gastrin releasing peptide receptor or reducing 1Y isoform activation may reduce opioid-induced pruritis

Background: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between μ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific μ-opioid receptor isoforms which interact with gastrin releasing peptide receptor.

Methods: Reverse transcription polymerase chain reaction was performed on human spinal cord complimentary DNA from two human cadavers. Calcium responses to morphine (1 μM) were examined using calcium imaging microscopy on human cells (HEK293) coexpressing gastrin releasing peptide receptor and different human μ-opioid receptor isoforms. The authors assessed morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine (0.3 nmol) and a transactivator of transcription peptide designed from C-terminal sequences of 1Y isoform (0, 0.1, and 0.4 nmol).

Results: The authors demonstrated 1Y expression in the spinal cord dorsal horn. Morphine administration evoked a calcium response (mean ± SD) (57 ± 13 nM) in cells coexpressing both gastrin releasing peptide receptor and the 1Y isomer. This was blocked by 10 μM naltrexone (0.7 ± 0.4 nM; P < 0.0001), 1 μM gastrin-releasing peptide receptor antagonist (3 ± 2 nM; P < 0.0001), or 200 μM 1Y-peptide (2 + 2 nM; P < 0.0001). In mice, 0.4 nmol 1Y-peptide significantly attenuated morphine-induced scratching behaviors (scratching bouts, vehicle vs. 1Y-peptide) (92 ± 31 vs. 38 ± 29; P = 0.011; n = 6 to 7 mice per group), without affecting morphine antinociception in warm water tail immersion test (% of maximum possible effect) (70 ± 21 vs. 67 ± 22; P = 0.80; n = 6 mice per group).

Conclusions: Human μ-opioid receptor 1Y isomer is a C-terminal splicing variant of Oprm1 gene identified in human spinal cord. Cross-talk between 1Y and gastrin releasing peptide receptor is required for mediating opioid-induced pruritus. Disrupting the cross talk may have implications for therapeutic uncoupling of desired analgesic effects from side effects of opioids.