Xian-Yu Liu1, Yehuda Ginosar, Joseph Yazdi, Alexander Hincker, Zhou-Feng Chen. 1. 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.) SpineMore Surgical Associates, St. Louis, Missouri (J.Y.).
Abstract
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.
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 7mice 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.
Authors: Svetlana A Shabalina; Dmitri V Zaykin; Pavel Gris; Aleksey Y Ogurtsov; Josee Gauthier; Kyoko Shibata; Inna E Tchivileva; Inna Belfer; Bikashkumar Mishra; Carly Kiselycznyk; Margaret R Wallace; Roland Staud; Nikolay A Spiridonov; Mitchell B Max; David Goldman; Roger B Fillingim; William Maixner; Luda Diatchenko Journal: Hum Mol Genet Date: 2008-12-22 Impact factor: 6.150
Authors: Leigh A Nattkemper; Zhong-Qiu Zhao; Anna J Nichols; Alexandru D P Papoiu; Carol A Shively; Zhou-Feng Chen; Gil Yosipovitch Journal: J Invest Dermatol Date: 2013-04-04 Impact factor: 8.551
Authors: Dorottya Ádám; József Arany; Kinga Fanni Tóth; Balázs István Tóth; Attila Gábor Szöllősi; Attila Oláh Journal: Int J Mol Sci Date: 2022-04-08 Impact factor: 6.208
Authors: Arpana Agrawal; Paul W Jeffries; A Benjamin Srivastava; Vivia V McCutcheon; Michael T Lynskey; Andrew C Heath; Elliot C Nelson Journal: J Neurosci Res Date: 2020-05-28 Impact factor: 4.164
Authors: Miriam M Düll; Katharina Wolf; Marcel Vetter; Peter Dietrich; Markus F Neurath; Andreas E Kremer Journal: Front Med (Lausanne) Date: 2021-04-14
Authors: Shan Liu; Wen-Jia Kang; Anna Abrimian; Jin Xu; Luca Cartegni; Susruta Majumdar; Patrick Hesketh; Alex Bekker; Ying-Xian Pan Journal: Biomolecules Date: 2021-10-15