Szolcsányi János
Prog Drug Res. 2014;68:1-37. doi: 10.1007/978-3-0348-0828-6_1.
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.
辣椒素是红辣椒中的辛辣成分，它不仅成为神经科学领域的一个“热门”话题，而且其与新靶点相关的独特作用为制药行业开启了引入新型镇痛药新篇章的大门。经过一系列转化研究，拥有1000多项专利并开展了多项临床试验后，8%辣椒素皮肤贴剂上市，其在某些严重神经病理性疼痛状态下的持久局部镇痛效果现已得到充分证实。本章一方面基于作者在该领域50年的经验概述了历史背景，另一方面强调了伤害性感觉神经元在药物生理学和分子药理学方面的新领域、迷人前景。列出了辣椒素对C类多模式伤害感受器（CMH）、C类机械不敏感感受器（CHMi）和沉默C类伤害感受器作用的证据，并展示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征。提出了新生儿辣椒素预处理得出误导性结论的证据。概述了克隆辣椒素受体“瞬时受体电位香草酸亚型1”（TRPV1）带来的前景，并总结了辣椒素和其他TRPV1激动剂产生持久功能、超微结构和神经末梢损伤作用背后的潜在分子机制。神经源性炎症和一长串“辣椒素敏感”组织反应是由表达肽能TRPV1的神经末梢的非传统双感觉 - 传出功能介导的，这与在神经调节中具有单向作用的经典传出和感觉神经末梢不同。详细讨论了辣椒素的体温调节作用。有人认为，由于有害热阈值升高导致的体温过高和烧伤风险是一些TRPV1拮抗剂的主要障碍，这些障碍是可以克服的。TRPV1阳离子通道特殊的“多位点”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新篇章现已得到支持，可用于缓解持续性病理性疼痛状态。
