Nassenstein Christina, Kwong Kevin, Taylor-Clark Thomas, Kollarik Marian, Macglashan Donald M, Braun Armin, Undem Bradley J
Johns Hopkins Allergy and Asthma Center 5501 Hopkins Bayview Circle Baltimore, MD 21224, USA.
J Physiol. 2008 Mar 15;586(6):1595-604. doi: 10.1113/jphysiol.2007.148379. Epub 2008 Jan 24.
Transient receptor potential (TRP) A1 and TRPM8 are ion channels that have been localized to afferent nociceptive nerves. These TRP channels may be of particular relevance to respiratory nociceptors in that they can be activated by various inhaled irritants and/or cold air. We addressed the hypothesis that mouse vagal sensory nerves projecting to the airways express TRPA1 and TRPM8 and that they can be activated via these receptors. Single cell RT-PCR analysis revealed that TRPA1 mRNA, but not TRPM8, is uniformly expressed in lung-labelled TRPV1-expressing vagal sensory neurons. Neither TRPA1 nor TRPM8 mRNA was expressed in TRPV1-negative neurons. Capsaicin-sensitive, but not capsaicin-insensitive, lung-specific neurons responded to cinnamaldehyde, a TRPA1 agonist, with increases in intracellular calcium. Menthol, a TRPM8 agonist, was ineffective at increasing cellular calcium in lung-specific vagal sensory neurons. Cinnamaldehyde also induced TRPA1-like inward currents (as measured by means of whole cell patch clamp recordings) in capsaicin-sensitive neurons. In an ex vivo vagal innervated mouse lung preparation, cinnamaldehyde evoked action potential discharge in mouse vagal C-fibres with a peak frequency similar to that observed with capsaicin. Cinnamaldehyde inhalation in vivo mimicked capsaicin in eliciting strong central-reflex changes in breathing pattern. Taken together, our results support the hypothesis that TRPA1, but not TRPM8, is expressed in vagal sensory nerves innervating the airways. TRPA1 activation provides a mechanism by which certain environmental stimuli may elicit action potential discharge in airway afferent C-fibres and the consequent nocifensor reflexes.
瞬时受体电位（TRP）A1和TRPM8是定位于传入伤害性神经的离子通道。这些TRP通道可能与呼吸道伤害感受器特别相关，因为它们可被各种吸入性刺激物和/或冷空气激活。我们探讨了以下假设：投射到气道的小鼠迷走感觉神经表达TRPA1和TRPM8，并且它们可通过这些受体被激活。单细胞逆转录聚合酶链反应（RT-PCR）分析显示，TRPA1信使核糖核酸（mRNA）在肺标记的表达瞬时受体电位香草酸亚型1（TRPV1）的迷走感觉神经元中均匀表达，而TRPM8则不然。TRPA1和TRPM8的mRNA在TRPV1阴性神经元中均未表达。对辣椒素敏感而非不敏感的肺特异性神经元对TRPA1激动剂肉桂醛产生反应，细胞内钙增加。TRPM8激动剂薄荷醇在增加肺特异性迷走感觉神经元细胞内钙方面无效。肉桂醛还在对辣椒素敏感的神经元中诱导出类似TRPA1的内向电流（通过全细胞膜片钳记录测量）。在离体迷走神经支配的小鼠肺标本中，肉桂醛诱发小鼠迷走C纤维动作电位发放，其峰值频率与辣椒素观察到的相似。体内吸入肉桂醛模拟辣椒素，引发强烈的呼吸模式中枢反射变化。综上所述，我们的结果支持以下假设：支配气道的迷走感觉神经表达TRPA1而非TRPM8。TRPA1激活提供了一种机制，通过该机制某些环境刺激可引发气道传入C纤维动作电位发放以及随之而来的伤害感受反射。
