人脊髓 μ 阿片受体 1Y 同工型与胃泌素释放肽受体的串扰介导阿片类药物引起的搔抓行为。
Cross-talk between Human Spinal Cord μ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior.
机构信息
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.).
出版信息
Anesthesiology. 2019 Aug;131(2):381-391. doi: 10.1097/ALN.0000000000002776.
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.
背景
尽管脊髓阿片类药物是安全有效的，但瘙痒是常见且令人痛苦的。作者之前在小鼠脊髓中证明，μ-阿片受体 1D 同工型与胃泌素释放肽受体之间的相互作用介导吗啡引起的搔抓。1D 的 C 端抑制吗啡引起的搔抓而不影响镇痛。作者假设人类脊髓中也存在与胃泌素释放肽受体相互作用的瘙痒特异性μ-阿片受体同工型。
方法
对来自两个人类尸体的人类脊髓 cDNA 进行逆转录聚合酶链反应。使用钙成像显微镜在共表达胃泌素释放肽受体和不同人类μ-阿片受体同工型的人类细胞（HEK293）上检查吗啡（1 μM）引起的钙反应。作者评估了鞘内注射吗啡（0.3 nmol）和从 1Y 同工型 C 端序列设计的转录激活肽后，小鼠的吗啡诱导搔抓行为和热镇痛。
结果
作者证明了脊髓背角中的 1Y 表达。给予吗啡后，共表达胃泌素释放肽受体和 1Y 同工型的细胞引起钙反应（均值±标准差）（57±13 nM）。这被 10 μM 纳曲酮（0.7±0.4 nM；P<0.0001）、1 μM 胃泌素释放肽受体拮抗剂（3±2 nM；P<0.0001）或 200 μM 1Y-肽（2+2 nM；P<0.0001）阻断。在小鼠中，0.4 nmol 1Y-肽显著减弱吗啡诱导的搔抓行为（搔抓发作，载体与 1Y-肽）（92±31 与 38±29；P=0.011；每组 6 至 7 只小鼠），而不影响吗啡在温水尾浸试验中的抗伤害作用（最大可能效果的%）（70±21 与 67±22；P=0.80；每组 6 只小鼠）。
结论
人类μ-阿片受体 1Y 同工型是在人类脊髓中鉴定的 Oprm1 基因的 C 端剪接变体。1Y 与胃泌素释放肽受体之间的串扰是介导阿片类药物引起瘙痒所必需的。阻断这种串扰可能对治疗性地将所需的镇痛作用与阿片类药物的副作用分离具有重要意义。
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