辣椒素和感觉神经元:一个历史的视角。

János Szolcsányi
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引用次数: 48

摘要

红辣椒中的辛辣成分辣椒素不仅成为神经科学的“热门”话题,而且其与靶标相关的新独特作用为制药业打开了镇痛药的新篇章。经过数个系列的转化努力,超过1000项专利和临床试验,8%辣椒素皮肤贴片进入市场,其对一些严重神经性疼痛状态的持久局部镇痛作用现已得到证实。这一导论章节一方面概述了作者在这一领域50年经验的历史背景,另一方面强调了伤害感觉神经元的药物生理学和分子药理学的新范围,迷人的观点。辣椒素对c -多模态伤害感受器(CMH)、c -机械不敏感(CHMi)和沉默c -伤害感受器的影响的证据被列出,并证明了辣椒素诱导的伤害感受器阻断作用的特征。总结了全身、神经周围、局部、鞘内和体外治疗后伤害感受器阻断作用的共同和不同特点。证据从新生儿辣椒素预处理得出的误导性结论提出。综述了辣椒素受体TRPV1 (Transient receptor Potential Vanilloid 1)的克隆前景,并对辣椒素和其他TRPV1激动剂持久的功能、超微结构和神经末梢损伤作用背后的潜在分子机制进行了总结。神经源性炎症和一系列“辣椒素敏感”组织反应是由表达肽能trpv1的神经末梢的非正统的双重感觉-传出功能介导的,这种功能不同于经典的单向神经调节的传出和感觉神经末梢。详细讨论了辣椒素的体温调节作用。这表明,由于高温和因有毒热阈值提高而导致的烧伤风险是一些TRPV1拮抗剂的主要障碍,它们是可以克服的。TRPV1阳离子通道特殊的“多空间”门控功能为阻断TRPV1的化学激活而不影响其对物理刺激的反应性提供了结构基础。针对伤害感受器的潜在镇痛药物的新篇章现在已经支持在持续的病理性疼痛状态下缓解疼痛。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Capsaicin and sensory neurones: a historical perspective.

Capsaicin, the pungent ingredient of red pepper has become not only a "hot" topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8% capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author's 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor "Transient Receptor Potential Vanilloid 1" (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of "capsaicin-sensitive" tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special "multisteric" gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states.

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