Related Experiment Video
Updated: Jan 22, 2026
Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis
Published on: July 3, 2015
Cross-talk between Human Spinal Cord μ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates
Xian-Yu Liu1, Yehuda Ginosar, Joseph Yazdi
1From 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.) SpineMore Surgical Associates, St. Louis, Missouri (J.Y.).
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.
Insights
Spinal opioids cause itching via interactions between the mu-opioid receptor 1Y isomer and gastrin-releasing peptide receptor. Targeting this pathway may reduce opioid-induced itch without affecting pain relief.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Spinal opioids are effective analgesics but commonly cause pruritus (itching).
- Previous research identified interactions between mu-opioid receptor 1D and gastrin-releasing peptide receptor mediating morphine-induced scratching in mice.
- The C-terminal of 1D was found to inhibit scratching without altering analgesia.
Purpose of the Study:
- To investigate if human spinal cord contains itch-specific mu-opioid receptor isoforms.
- To determine if these isoforms interact with the gastrin-releasing peptide receptor (GRPR).
- To explore the potential of targeting these interactions for therapeutic benefit.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) on human spinal cord cDNA.
- Calcium imaging microscopy in HEK293 cells coexpressing GRPR and human mu-opioid receptor isoforms in response to morphine.
- Assessment of morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine and a peptide targeting the 1Y isoform.
Main Results:
- The mu-opioid receptor 1Y isomer was detected in the human spinal cord dorsal horn.
- Morphine induced a calcium response in cells coexpressing GRPR and 1Y, which was blocked by naltrexone, a GRPR antagonist, or the 1Y-peptide.
- In mice, the 1Y-peptide significantly reduced morphine-induced scratching without affecting analgesia.
Conclusions:
- The human mu-opioid receptor 1Y isomer, a variant of Oprm1, is expressed in the spinal cord.
- Cross-talk between 1Y and GRPR mediates opioid-induced pruritus.
- Disrupting this 1Y-GRPR interaction could decouple analgesic effects from side effects like itching.
Related Concept Videos
01:22Opioid Receptors: Overview
01:15Opioid Analgesics: Synthetic and Semisynthetic Opioids
01:39Receptor-mediated Endocytosis
01:20Receptor-mediated Endocytosis
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
01:31Internal Receptors
01:20Opioid Analgesics: Morphine and Other Natural Cogeners