Contribution of Sigma Receptor Activation to Neuropathic Pain

Sigma 受体激活对神经病理性疼痛的影响

• 批准号: 8305717
• 负责人: HSIANG-EN WU
• 金额: $ 14.28万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305717
• 关键词: Absence of pain sensation; Afferent Neurons; Attenuated; Behavior; Behavioral; Binding; Biological; Calcium; Calcium Signaling; Cell Death; Cells; Control Animal; Cytophotometry; Dedications; Depressed mood; Electrophysiology (science); Endoplasmic Reticulum; Environment; Esthesia; Evaluation; Familiarity; Formalin; Foundations; Freund' s Adjuvant; Functional disorder; Funding; Future; Gene Expression; Generations; Goals; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Infusion procedures; Injection of therapeutic agent; Injury; Instruction; Investigation; Knowledge; Life; Ligands; Ligation; Measures; Mentors; Methods; Mitochondria; Modeling; Molecular; Molecular Biology; Morphine; Nerve; Neuroglia; Neurons; Neuropharmacology; Nociception; Opioid; Pain; Pain Research; Pathway interactions; Pattern; Peptides; Peripheral nerve injury; Process; Productivity; Rattus; Receptor Activation; Regulation; Research; Research Personnel; Research Training; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Shapes; Signal Transduction; Spinal Ganglia; Spinal nerve structure; Subgroup; Testing; Training Programs; Transcript; Trauma; Western Blotting; Wisconsin; addiction; cell type; cellular imaging; clinically relevant; in vivo; inflammatory neuropathic pain; inflammatory pain; medical schools; nerve injury; neuronal cell body; neuronal excitability; neurotransmitter release; novel therapeutics; pain behavior; pain inhibition; painful neuropathy; patch clamp; programs; protein expression; radioligand; receptor; research study; selective expression; sigma receptors; skills; voltage

This application proposes a program of training and research to expand the candidate's future prospects in achieving independence in pain research. The candidate has demonstrated his dedication to research and his initiative and high productivity in prior investigations, but he requires familiarity with a broader range of experimental approaches to fully explore pain pathophysiology and to be competitive in independent funding. The mentor. Dr. Hogan, is a well-established clinician/scientist, and the dynamic research surrounding at Medical College of Wisconsin provides an ideal environment for the candidate to become a highly productive independent researcher. The program will help the candidate to accomplish the following goals: 1) establish modern scientific knowledge, acquire the newest research skills, and refine critical analytical abilities; 2) provide coursework and interactive settings that will expand independence as a scientist; 3) apply this new knowledge to examine the role of sigma receptors (aR) in traumatic painful neuropathy and inflammatory pain. Sensory neurons, including their somata in the dorsal root ganglion (DRG), develop abnormal function following nerve trauma and inflammation that contributes to pain. Although numerous triggers have been proposed for initiating these debilitating conditions, none has been established as a clinically relevant pathway. The proposed studies will examine the central hypothesis that activation of alR receptors in nociceptive sensory neurons contributes to neuropathic and inflammatory pain through inhibition of calcium signaling. Specific Aim 1 will determine the effects of olR ligands on behavioral hyperalgesia after nerve injury and injection of complete Freund's adjuvant. Specific Aim 2 will define the expression of olR in primary sensory neurons under baseline conditions. Specific Aim 3 will examine functional consequences of olR activation in vitro, including effects on inward Ca2+ currents, neuronal excitability, and intracellular Ca2+ signaling. Specific Aim 4 will identify expression and functional contributions of alR activity to changes after nerve injury and inflammation. These proposed experiments will employ convergent approaches including molecular and cell biological methods, immunohistochemical and live cell imaging, electrophysiological recording, and behavioral evaluation. The program will establish the candidate's new expertise in electrophysiology, molecular biology, and neuropharmacology and provide the foundation for establishing an independent research program considering olR in pain, opioid tolerance, and addiction. RELEVANCE (See instructions): Exploration of the contributions of al R in prinnary sensory neurons to pain sensation may provide a new therapeutic pathway for pain conditions that are resistant to currently available treatments.

本申请提出了一个培训和研究计划，以扩大候选人的未来前景