FUNCTIONAL REGULATION OF OPIOID SIGNALLING

阿片类信号传导的功能调节

• 批准号: 7668243
• 负责人: EVA V VARGA
• 金额: $ 15.96万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7668243
• 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.

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