CAPSAICIN RECEPTOR SUBTYPES IN PAIN TRANSDUCTION

疼痛传导中的辣椒素受体亚型

• 批准号: 2850668
• 负责人: MARK A SCHUMACHER
• 金额: $ 14.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2850668
• 关键词: RNA splicing; RNase protection assay; Xenopus oocyte; afferent nerve; capsaicin; complementary DNA; drug adverse effect; drug hypersensitivity; drug receptors; genetic mapping; genome; heat stimulus; in situ hybridization; laboratory rat; messenger RNA; neural transmission; neurons; northern blottings; pain; peripheral nervous system; polymerase chain reaction; southern blotting; spinal ganglion; tissue /cell culture; voltage /patch clamp

Unwanted side effects such as central nervous system depression and risk of addiction limit the ability to manage acute and chronic pain states even if adequate pain relief has been achieved. Since pain can originate from the persistent activation of peripheral nociceptive neurons, the development of new therapies that can selectively block pain at the primary afferent nerve terminal would represent a novel and significant achievement in pain management. We have recently characterized a cDNA clone encoding a vanilloid (capsaicin) receptor expressed in peripheral sensory neurons that transduce pain (Nature 389: 816-824, 1997). This cDNA termed, "vanilloid receptor type-1", (VR1) encodes an ion channel which confers several important properties relevant to peripheral pain transduction. It is activated by a class of compounds such as capsaicin, which are painful if topically applied to humans but following repeated application, produce analgesia, VR-1 is also activated by intense heat in the range that is associated with the sensation of burning pain and is potentiated under conditions of low pH as exists with disorders of inflammation and infection. We will test the hypothesis that vanilloid receptors arise from a common gene by characterizing genomic clones encoding vanilloid receptors. In the preliminary results, we demonstrate an additional subtype cDNA (termed VR-2). Therefore, by expressing VR-2 in Xenopus oocytes, we will test the hypothesis that VR-2 encodes a vanilloid receptor with responses to noxious chemical and heat stimuli that are distinct from VR-1 and that VR-2 is differentially expressed in nociceptive neurons by in situ hybridization and quantitate those difference by RT-PCR. Since capsaicin is used as topical analgesics to treat pain, characterization of vanilloid receptor subtypes should provide important insight into the advancement of therapies designed to selectively block pain.

不必要的副作用，如中枢神经系统抑郁和成瘾风险，限制了处理急性和慢性疼痛状态的能力，即使已经达到了足够的疼痛缓解。由于疼痛可能源于外周伤害性神经元的持续激活，因此在初级传入神经末梢选择性阻断疼痛的新疗法的发展将代表疼痛管理方面的一项新的重大成就。我们最近描述了一个编码外周感觉神经元中表达的辣椒素受体的cDNA克隆（Nature 389: 816-824, 1997）。这种被称为“香草样受体1型”（VR1）的cDNA编码一个离子通道，该通道赋予与外周疼痛转导相关的几个重要特性。它被一类化合物激活，如辣椒素，如果局部应用于人类是痛苦的，但反复应用后，产生镇痛作用，VR-1也被与灼痛感相关的范围内的高温激活，并在低pH值条件下增强，如存在炎症和感染障碍。我们将通过描述编码香草受体的基因组克隆来验证香草受体来自一个共同基因的假设。在初步结果中，我们展示了一个额外的cDNA亚型（称为VR-2）。因此，通过在非洲爪蟾卵母细胞中表达VR-2，我们将验证以下假设：VR-2编码的香草受体对有害化学和热刺激的反应与VR-1不同，VR-2在伤害性神经元中表达差异，并通过原位杂交和RT-PCR量化这些差异。由于辣椒素被用作局部止痛剂来治疗疼痛，因此对香兰素受体亚型的表征应该为选择性阻断疼痛的治疗方法的进展提供重要的见解。