Purinergic Mechansism of Nociception

伤害感受的嘌呤能机制

• 批准号: 6805989
• 负责人: Christopher Nick Honda
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805989
• 关键词: afferent nerve; analgesics; antisense nucleic acid; drug design /synthesis /production; immunocytochemistry; laboratory rat; mass spectrometry; pain; purinergic receptor; receptor expression; stimulus /response; western blottings

DESCRIPTION (provided by applicant): This Stage 1 Cebra application seeks to test the feasibility of simultaneous functional down-regulation of two ATP gated ion channels present in the subset of nociceptive sensory neurons. The P2X2 and P2X3 purinergic receptors arechosen for investigation because recent studies suggest that many sensory neurons behave as if they express these two receptors in a heteromultimeric configuration (P2X2/3), and because antisense oligonucleotide knockdown of P2X3 alone results in modest attenuation of some nociceptive behaviors. The underlying hypotheses of this proposal is that simultaneous knockdown of P2X2 and P2X3 purinergic receptors is an effective approach to interfere with nociceptive processing, and that it is a more efficient way to target heteromeric receptor configurations than approaches targeting either P2X2 or P2X3 receptors alone. An antisense oligonucleotide approach combined with immunohistochemical, behavioral, and electrophysiological measures will be used to determine whether simultaneous delivery of antisense oligonucleotides for P2X2 and P2X3 will decrease the expression of P2X2 and P2X3 in sensory neurons and reduce nociceptive behaviors. In addition, these studies will determine for the first time whether antisense treatment will alter the response properties of functionally identified sensory neurons with intact receptive fields. In making this proposal, existing methodologies will be integrated and applied as a new paradigm. Findings from these experiments could contribute to the development of viable therapeutic alternatives to the use of analgesic agents such as opiate compounds that have high potential for tolerance and dependence.

描述(由申请人提供)： CEBRA的这一阶段应用试图测试同时功能下调存在于伤害性感觉神经元亚群中的两个ATP门控离子通道的可行性。之所以选择P2X2和P2X3受体作为研究对象，是因为最近的研究表明，许多感觉神经元的行为就像是以异多聚体的形式表达这两种受体(P2X2/3)，并且因为单独的反义寡核苷酸敲除P2X3会导致一些伤害性行为的适度减弱。这一建议的基本假设是，同时敲除P2X2和P2X3嘌呤能受体是干扰伤害性加工的有效方法，并且比仅针对P2X2或P2X3受体的方法更有效地靶向异构体受体配置。采用反义寡核苷酸方法，结合免疫组织化学、行为学和电生理学方法，研究同时给予P2X2和P2X3反义寡核苷酸是否会减少感觉神经元中P2X2和P2X3的表达，从而减少伤害性行为。此外，这些研究将首次确定反义治疗是否会改变具有完整感受野的功能识别感觉神经元的反应特性。在提出这一建议时，将把现有方法作为一种新的范式加以整合和应用。这些实验的发现可能有助于开发可行的治疗替代药物，以取代使用具有高耐受性和依赖性的止痛剂，如阿片类化合物。