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.

不受欢迎的副作用，如中枢神经系统抑郁和成瘾风险，限制了管理急性和慢性疼痛状态的能力，即使已经实现了足够的疼痛缓解。由于疼痛可以起源于外周伤害性感觉神经元的持续激活，因此发展能够选择性地阻断初级传入神经末梢的疼痛的新疗法将是疼痛管理方面的一项新的重大成就。我们最近鉴定了一个编码香草素(辣椒素)受体的cDNA克隆，该受体在外周感觉神经元中表达，传递疼痛(自然389：816-824,1997)。该基因被称为“香草酸受体-1”(VR1)，它编码一个离子通道，该通道具有与外周疼痛转导相关的几个重要特性。VR-1是由一类化合物激活的，如辣椒素，如果局部应用于人类是疼痛的，但重复使用后会产生止痛，VR-1也可以在与灼热痛感相关的高热范围内激活，并在低pH条件下增强，如炎症和感染疾病。我们将通过描述编码香草素受体的基因组克隆来检验香草素受体起源于共同基因的假设。在初步结果中，我们展示了一个额外的亚型cDNA(称为VR-2)。因此，通过在非洲爪哇卵母细胞中表达VR-2，我们将验证VR-2编码的香草素受体与VR-1不同的化学和热伤害刺激的反应，以及VR-2在伤害性神经元中的差异表达的假说，并通过RT-PCR对这些差异进行定量。由于辣椒素被用作局部止痛剂来治疗疼痛，香草素受体亚型的特征应该为设计用于选择性阻断疼痛的治疗的进展提供重要的洞察。