Contribution of Sigma Receptor Activation to Neuropathic Pain

描述(由申请者提供)：本申请提出了一个培训和研究计划，以扩大候选人在疼痛研究中实现独立的未来前景。这位候选人在之前的研究中展示了他对研究的奉献精神以及他的主动性和高生产率，但他需要熟悉更广泛的实验方法，以全面探索疼痛病理生理学，并在独立资金方面具有竞争力。导师。霍根博士是一位久负盛名的临床医生/科学家，威斯康星医学院充满活力的研究环境为候选人成为一名高效的独立研究人员提供了理想的环境。该计划将帮助候选人实现以下目标：1)建立现代科学知识，获得最新的研究技能，并提高批判性分析能力；2)提供课程作业和互动环境，以扩大科学家的独立性；3)应用这一新知识来研究Sigma受体(AR)在创伤性痛性神经病变和炎症性疼痛中的作用。感觉神经元，包括它们在背根神经节(DRG)中的体细胞，在神经损伤和炎症后发展异常功能，从而导致疼痛。虽然已经提出了许多启动这些衰弱条件的触发因素，但没有一个被确定为与临床相关的途径。这项拟议的研究将检验中心假设，即伤害性感觉神经元上ALR受体的激活通过抑制钙信号而参与神经病理性和炎症性疼痛。具体目标1将确定OLR配体在神经损伤和注射完全弗氏佐剂后对行为痛敏的影响。具体目标2将定义在基线条件下OLR在初级感觉神经元中的表达。具体目标3将在体外检测OLR激活的功能后果，包括对内向钙电流、神经元兴奋性和细胞内钙信号的影响。具体目标4将确定ALR活性在神经损伤和炎症后的变化中的表达和功能贡献。这些拟议的实验将采用融合的方法，包括分子和细胞生物学方法、免疫组织化学和活细胞成像、电生理记录和行为评估。该计划将建立候选人在电生理学、分子生物学和神经药理学方面的新专业知识，并为建立一个考虑疼痛、阿片类药物耐受性和成瘾的独立研究计划奠定基础。公共卫生相关性：探索初级感觉神经元中ALR对痛觉的贡献可能为目前无法治疗的疼痛状况提供一种新的治疗途径。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Exploration of the contributions of alR in primary sensory neurons to pain sensation may provide a new therapeutic pathway for pain conditions that are resistant to currently available treatments.