CAPSAICIN RECEPTOR SUBTYPES IN PAIN TRANSDUCTION

疼痛传导中的辣椒素受体亚型

• 批准号: 6187810
• 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/6187810
• 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.

不需要的副作用，例如中枢神经系统抑郁症和成瘾风险，即使已经实现了足够的疼痛，也限制了管理急性和慢性疼痛状态的能力。 由于疼痛可以源于周围伤害性神经元的持续激活，因此可以选择性地阻止主要传入神经末端疼痛的新疗法的发展将代表疼痛管理中的新颖而重要的成就。 最近，我们表征了一个编码在传递疼痛的外周感觉神经元中表达的香草素（辣椒素）受体的cDNA克隆（自然389：816-824，1997）。 该cDNA称为“香草素受体Type-1”，（VR1）编码一个离子通道，该通道赋予了与周围疼痛转导相关的几种重要特性。 它被一类化合物（例如辣椒素）激活，辣椒素如果局部应用于人类，但经过重复应用后，它会产生镇痛，VR-1也被激活的范围内激活，这与燃烧疼痛的感觉有关，与炎症和感染的疾病有关，与燃烧疼痛的感觉相关，并且在低pH的情况下受到强化。 我们将通过表征编码香草素受体的基因组克隆来检验的假说，即香草素受体是由常见基因引起的。 在初步结果中，我们证明了另一种亚型cDNA（称为VR-2）。 因此，通过在爪蟾卵母细胞中表达VR-2，我们将测试以下假设：VR-2编码具有对有害的化学和热刺激的响应的香草素受体，它们与VR-1不同，并且VR-2通过原位杂交和差异差异在伤害性神经元中差异化，并通过rt-pcr差异。 由于辣椒素被用作局部镇痛药来治疗疼痛，因此，香草素受体亚型的表征应为旨在选择性地阻断疼痛的疗法的进步提供重要的见解。