CAPSAICIN RECEPTOR SUBTYPES IN PAIN TRANSDUCTION

疼痛传导中的辣椒素受体亚型

• 批准号: 6394145
• 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/6394145
• 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.

即使已经实现了充分的疼痛缓解，中枢神经系统抑制和成瘾风险等不需要的副作用也限制了处理急性和慢性疼痛状态的能力。 由于疼痛可能源自外周伤害性神经元的持续激活，因此开发能够选择性阻断初级传入神经末梢疼痛的新疗法将代表疼痛治疗方面的一项新颖且重大的成就。 我们最近鉴定了编码香草酸（辣椒素）受体的 cDNA 克隆，该受体在外周感觉神经元中表达，可传导疼痛（Nature 389：816-824，1997）。 这种被称为“1 型香草素受体”(VR1) 的 cDNA 编码一个离子通道，该离子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，例如辣椒素，如果局部应用于人类，会感到疼痛，但重复使用后会产生镇痛作用，VR-1 也会被与灼痛感相关的强热激活，并且在炎症和感染性疾病存在的低 pH 条件下增强。 我们将通过表征编码香草酸受体的基因组克隆来检验香草酸受体源自共同基因的假设。 在初步结果中，我们展示了另一种 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，我们将测试这样的假设：VR-2 编码一种香草酸受体，其对有毒化学物质和热刺激的反应与 VR-1 不同，并且 VR-2 通过原位杂交在伤害性神经元中差异表达，并通过 RT-PCR 定量这些差异。 由于辣椒素被用作局部镇痛药来治疗疼痛，香草酸受体亚型的表征应该为选择性阻止疼痛的疗法的进展提供重要的见解。