MECHANISMS OF DESENSITIZATION OF MOR1D-GRPR CROSSTALK

描述（由申请人提供）：本提案的长期目标是了解阿片类药物诱导的瘙痒所需的MOR 1D-GRPR串扰脱敏的信号传导机制。脊髓或硬膜外阿片类药物引起的瘙痒是疼痛管理中普遍存在的副作用，其潜在的分子和细胞机制知之甚少。MOR 1D是一种Gi蛋白偶联的μ阿片受体亚型，通过交叉激活脊髓中的瘙痒特异性受体胃泌素释放肽受体（GRPR）介导吗啡诱导的瘙痒。我们发现磷酸化是MOR 1D-GRPR信号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MOR 1D-GRPR信号传导的影响。目的2将确定GRK 2/arrestin 2在MOR 1D-GRPR脱敏中的功能。目的3将研究PKC在MOR 1D-GRPR脱敏中的作用，并验证PKC和GRK 2/arrestin 2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、生物物理学、电生理学和行为学方法来解决这些问题。我们的研究将提高对MOR 1D-GRPR脱敏的信号传导机制的理解，并可能为治疗阿片类药物诱导的瘙痒而不影响阿片类药物镇痛的新疗法提供重要信息。

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.