FUNCTIONAL REGULATION OF OPIOID SIGNALLING

阿片类信号传导的功能调节

• 批准号: 8025976
• 负责人: EVA V VARGA
• 金额: $ 16.29万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025976
• 关键词: Adenylate Cyclase; Afferent Neurons; Agonist; Analgesics; BDKRB2 gene; Binding Sites; Bradykinin Receptor; Capsaicin; Cell Line; Cells; Chronic; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dinoprostone; Dynamin 2; Dynorphin A; Dynorphins; Event; Forskolin; Future; Hand; Human; Hyperalgesia; In Vitro; Investigation; Lead; Mediating; Modeling; Molecular; Morphine; Neonatal; Neuromodulator; Neuronal Plasticity; Neurons; Neurotransmitters; Nociception; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Pain; Pathway interactions; Physiological; Play; Preparation; Process; Protein Kinase; Protein Kinase Inhibitors; Proteins; Proto-Oncogene Proteins c-raf; Rattus; Receptor Signaling; Recombinants; Regulation; Role; Sensory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Spinal; Spinal Cord; Stimulus; Testing; Up-Regulation; Work; allodynia; analog; biphalin; central pain; chronic pain; endogenous opioids; in vitro testing; inhibitor/antagonist; neurotransmitter release; novel; protein kinase inhibitor; receptor; receptor coupling; research study; trafficking

Sustained morphine treatment was shown to increase the concentration of excitatory Gs protein-coupled neuromodulators (such as PGE2 and dynorphin) and augment pain neurotransmitter release in the spinal cord. In Project C we will investigate the role of cAMP-regulated signaling pathways in the regulation of pain neurotransmitter (CGRP) release from cultured neonatal rat primary sensory (DRG) neurons by PGE2 and a non-opioid fragment of spinal dynorphin, dyn2-13. In addition, since earlier we have shown that sustained morphine treatment leads to a Raf-1 -mediated sensitization of adenylyl cyclase(s) (AC superactivation) towards excitatory agents in recombinant cells, in Project C we also will investigate the physiological role of Raf-1-mediated AC superactivation in the sensitization of basal and/or capsaicin-evoked CGRP release from sensory neurons after sustained morphine-treatment. We hypothesize that Raf-1-mediated AC superactivation sensitizes primary sensory neurons to Gs protein-coupled neuromodulators leading to augmented basal and/or evoked CGRP release upon sustained morphine treatment. To evaluate this hypothesis we shall I. investigate the role of Raf-1 in the sensitization of cAMP formation in cultured neonatal rat DRG neurons toward the Gs protein-coupled excitatory neuromodulators, PGE2 and dyn2-13; II. test the role of cAMP, cAMP-dependent protein kinase (PKA) and Raf-1 in the regulation of basal and/or capsaicinevoked CGRP release by PGE2 and dyn2-13 in cultured neonatal rat DRG neurons before and after sustained morphine treatment; and III. study the effect of selected novel compounds - prepared in the Synthetic Core and Project A - on cAMP concentration and basal and capsaicin-evoked CGRP release in cultured neonatal rat DRG neurons, before and after sustained opioid agonist treatment.

持续的吗啡处理显示出增加兴奋性Gs蛋白偶联的浓度， 神经调质（如PGE 2和强啡肽）和增加疼痛神经递质释放的脊髓 线.在项目C中，我们将研究cAMP调节的信号通路在疼痛调节中的作用 PGE_2和α-葡聚糖诱导培养的新生大鼠背根神经节（DRG）神经元释放CGRP 脊髓强啡肽的非阿片片段，dyn 2 -13。此外，自早些时候以来，我们已经表明， 吗啡处理导致Raf-1介导的腺苷酸环化酶敏化（AC超活化） 在项目C中，我们还将研究重组细胞中的兴奋剂的生理作用， Raf-1介导的AC超激活在基础和/或辣椒素诱发的CGRP释放增敏中的作用 持续吗啡治疗后的感觉神经元。我们假设Raf-1介导的AC 超激活使初级感觉神经元对Gs蛋白偶联的神经调质敏感， 增加的基础和/或诱发的CGRP释放持续吗啡治疗。评价这一 假设我们应该我。探讨Raf-1在培养的新生儿cAMP形成增敏中的作用 大鼠DRG神经元对Gs蛋白偶联的兴奋性神经调质PGE 2和dyn 2 -13的反应; II.测试 cAMP、cAMP依赖性蛋白激酶（PKA）和Raf-1在基础和/或辣椒素调控中的作用 PGE 2和dyn 2 -13在培养的新生大鼠背根神经节神经元前后释放CGRP 持续的吗啡治疗;和III.研究选定的新化合物的效果-在 合成核心和项目A -对cAMP浓度和基础和辣椒素诱发的CGRP释放的影响 培养的新生大鼠DRG神经元，在持续阿片受体激动剂治疗之前和之后。