Ionic mechanisms of TNFalpha-induced sensitization

TNFα诱导致敏的离子机制

• 批准号: 7546432
• 负责人: Maria Elena Morales
• 金额: $ 2.73万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546432
• 关键词: Accounting; Address; Affect; Afferent Neurons; Animal Model; Behavior assessment; Behavioral; Biochemical; Biological; Cells; Characteristics; Clinic; Condition; Data; Disease; Effectiveness; Generations; Human; Hypersensitivity; Immune; In Vitro; Infection; Inflammatory; Injection of therapeutic agent; Intestines; Ion Channel; Lead; Link; Measures; Mechanics; Mediating; Mediator of activation protein; Membrane; Mission; Mus; Neurons; Nociception; Nociceptors; Pain; Pathway interactions; Peripheral; Pharmaceutical Preparations; Preparation; Process; Property; Resistance; Rheumatoid Arthritis; Role; Signal Transduction; Sodium Channel; Spinal Ganglia; Stimulus; System; TNF gene; Testing; Tetrodotoxin; Training; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States National Institutes of Health; Wild Type Mouse; Work; behavioral sensitization; chronic pain; cytokine; human MAPK14 protein; human TNF protein; in vivo; multidisciplinary; nociceptive response; patch clamp; research study; response; response to injury; therapeutic target

DESCRIPTION (provided by applicant): The main objective of this study is to identify the mechanism(s) by which tumor necrosis factor-?- (TNF??) induces hypersensitivity. TNF? has been identified as a pro-nociceptive, pro-inflammatory cytokine, and anti-TNF? agents are currently used to treat painful inflammatory conditions which may, in part, be due to modulation of nociceptive signaling. The mechanism by which TNF? modulates nociception remains unknown. Recent work has demonstrated TNF? modulation of the tetrodotoxin-resistant Na+ channel a subunit, Nav1.8. This channel is primarily found in sensory neurons that detect painful stimuli, the primary afferent nociceptors, and is capable of altering excitability of dorsal root ganglia (DRG) neurons, a mechanism that could underlie behavioral hypersensitivity. Therefore, this proposal aims to examine the role of Nav1.8 in TNF? -induced behavioral hypersensitivity, to determine whether TNF? modulates DRG excitability, and to identify the necessity of Nav1.8 in this process. To this end, the proposed experiments will test the necessity of Nav1.8 in TNF? -induced mechanical and thermal hypersensitivity in vivo by behavioral assessment of hypersensitivity in Nav1.8-/- and wild-type littermate mice after intraplantar injection of TNF?. Further, because increased excitability is a mechanism by which hypersensitivity can be maintained, TNF? modulation of DRG excitability in vitro will be examined. These experiments will measure TNF? -induced alterations in excitability and examine the role of p38 MAPK in this process. Finally, the proposed experiments will then test the necessity of Nav1.8 in TNF? -induced modulation of DRG excitability by electrophysiological assessment of various membrane and AP properties in Nav1.8-/- and wild type DRG neurons. In accordance with the mission of the NIH, these studies are part of the long-term objective of identifying new potential targets for the treatment of painful conditions by understanding the biological mechanisms that underlie these conditions. These experiments can lead to enhancements in the treatment of pain, which is a costly and debilitating condition affecting millions of people.????

描述(申请人提供)：本研究的主要目的是确定肿瘤坏死因子-？-(肿瘤坏死因子？？)会导致过敏。肿瘤坏死因子？已被确定为一种促伤害性、促炎性细胞因子和抗肿瘤坏死因子？目前，药物被用来治疗疼痛的炎症状况，这可能部分是由于伤害性信号的调节。肿瘤坏死因子？调制伤害性感觉的机制仍不清楚。最近的研究已经证明了肿瘤坏死因子？河豚毒素抗性Na+通道a亚基Nav1.8的调制。这种通道主要存在于感觉神经元中，它探测疼痛刺激，这是主要的传入伤害性感受器，并能够改变背根神经节(DRG)神经元的兴奋性，这一机制可能是行为超敏的基础。因此，本研究旨在探讨Nav1.8在肿瘤坏死因子？诱导的行为过敏中的作用，以确定肿瘤坏死因子？调节DRG兴奋性，并确定Nav1.8在这一过程中的必要性。为此，拟议的实验将通过足底注射肿瘤坏死因子？后对Nav1.8-/-和野生型小鼠的超敏反应的行为学评估，来测试在活体内应用Nav1.8对肿瘤坏死因子？诱导的机械和温度超敏反应的必要性。此外，由于兴奋性增加是维持超敏反应的一种机制，因此，肿瘤坏死因子？我们将研究在体外对DRG兴奋性的调节。这些实验将测量肿瘤坏死因子？诱导的兴奋性变化，并检测p38MAPK在这一过程中的作用。最后，这些实验将通过电生理评估NAV1.8-/-和野生型DRG神经元的各种膜和AP特性来测试Nav1.8在肿瘤坏死因子？诱导的DRG兴奋性调节中的必要性。根据美国国立卫生研究院的使命，这些研究是长期目标的一部分，目的是通过了解这些疾病背后的生物机制来确定治疗这些疾病的新的潜在靶点。这些实验可以加强对疼痛的治疗，疼痛是一种影响数百万人的昂贵且令人虚弱的疾病。