MECHANISMS OF DESENSITIZATION OF MOR1D-GRPR CROSSTALK

MOR1D-GRPR串扰的脱敏机制

基本信息

批准号：
9144749
负责人：
ZHOUFENG CHEN
金额：
$ 41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144749
关键词：
ADRBK1 gene Acute Address Adverse effects Analgesics Area Behavioral Binding Biochemical Biological Assay Bombesin Receptor Calcium Cells Cesarean section Complex Coupled Electrophysiology (science)Fluorescence Resonance Energy Transfer G protein coupled receptor kinase GRP gene Genetic Health Image In Vitro Incidence Knockout Mice Laboratories Lead Mediating Modeling Molecular Molecular Genetics Morphine Mus Narcotic Antagonists Nature Neurons Opioid Opioid Analgesics Pain management Pathway interactions Patients Phosphorylation Play Postoperative Pain Pregnant Women Protein Isoforms Proteins Pruritus Receptor Cell Receptor Cross-Talk Receptor Signaling Regulation Role Signal Transduction Small Interfering RNA Spinal Spinal Cord System Testing Time arrestin 2 behavior test biophysical techniques desensitization design improved in vivo inhibitor/antagonist knock-down mu opioid receptors new therapeutic target novel novel therapeutics patch clamp receptor research study response tool

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the signaling mechanisms underlying desensitization of MOR1D-GRPR crosstalk, which is required for opioid-induced itch. Spinal or epidural opioid-induced itch is a prevalent side effect in pain management and the underlying molecular and cellular mechanisms are poorly understood. MOR1D, a Gi protein-coupled mu opioid receptor isoform, mediates morphine-induced itch through cross-activation of gastrin-releasing peptide receptor (GRPR), an itch-specific receptor in the spinal cord. This cross-talk leads to morphine-induced itch signaling We found that phosphorylation is a major mechanism underlying a rapid desensitization of MOR1D-GRPR signaling. In Aim 1, we will determine the effect of morphine-induced phosphorylation on MOR1D-GRPR signaling. Aim 2 will determine the function of GRK2/arrestin2 in MOR1D-GRPR desensitization. Aim 3 will examine the role of PKC in MOR1D-GRPR desensitization and test the hypothesis that PKC and GRK2/arrestin2 function independently. We will use a combination of mouse genetics, molecular, cellular, biochemical, biophysical, electrophysiological and behavioral approaches to address these questions. Our studies will improve understanding of the signaling mechanism underlying desensitization of MOR1D-GRPR, and may yield important information for novel therapeutics for treating opioid-induced itch without compromising opioid analgesia.

描述（由申请人提供）：该提案的长期目标是了解 MOR1D-GRPR 串扰脱敏的信号传导机制，这是阿片类药物引起的瘙痒所必需的。脊髓或硬膜外阿片类药物引起的瘙痒是疼痛治疗中常见的副作用，但其潜在的分子和细胞机制尚不清楚。 MOR1D 是一种 Gi 蛋白偶联 mu 阿片受体亚型，通过交叉激活胃泌素释放肽受体 (GRPR)（脊髓中的一种瘙痒特异性受体）介导吗啡引起的瘙痒。这种串扰导致吗啡诱导的瘙痒信号传导我们发现磷酸化是 MOR1D-GRPR 信号传导快速脱敏的主要机制。在目标 1 中，我们将确定吗啡诱导的磷酸化对 MOR1D-GRPR 信号传导的影响。目标 2 将确定 GRK2/arrestin2 在 MOR1D-GRPR 脱敏中的功能。目标 3 将检查 PKC 在 MOR1D-GRPR 脱敏中的作用，并检验 PKC 和 GRK2/arrestin2 独立发挥作用的假设。我们将结合小鼠遗传学、分子、细胞、生物化学、生物物理、电生理学和行为方法来解决这些问题。我们的研究将增进对 MOR1D-GRPR 脱敏信号机制的理解，并可能为治疗阿片类药物引起的瘙痒而不影响阿片类药物镇痛的新疗法提供重要信息。