TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus.
TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus.
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DOI：
10.1152/ajpgi.90530.2008
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Shaoyong Yu;A. Ouyang
中科院分区：
文献类型：
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作者：
Shaoyong Yu;A. Ouyang
缓激素（BK）激活感觉神经，引起痛觉过敏。瞬时受体电位A1 （TRPA1）在感觉神经中表达，介导冷、机械和化学伤害感受。TRPA1可被BK激活，TRPA1敲除小鼠对BK和机械性伤害感受的反应受损。然而，缺乏来自感觉神经末梢的直接证据。本研究旨在确定TRPA1在bk诱导的内脏机械超敏反应中的作用。在离体豚鼠食管迷走神经制备中进行迷走神经结节和颈静脉神经元动作电位的细胞外记录。记录食管扩张和化学灌注引起的传入神经动作电位的峰值频率并进行比较。BK激活大部分结节和所有颈静脉C纤维。这种激活是可重复的，并且与食管扩张反应的显著增加有关，这可以通过B2受体拮抗剂WIN64338来预防。TRPA1激动剂异硫氰酸烯丙酯（AITC）激活大多数bk阳性结节和颈静脉C纤维。这与对机械膨胀的短暂反应丧失和对第二次AITC灌注的脱敏有关。AITC脱敏和TRPA1抑制剂HC-030031预处理均能抑制bk诱导的机械超敏反应，但不影响bk在结节和颈静脉C纤维中的激活。相比之下，食道迷走神经传入阿德尔塔纤维对BK或AITC没有反应，并且在BK灌注后没有表现出机械超敏反应。这提供了直接来自内脏感觉传入神经末梢TRPA1介导bk诱导的机械超敏反应的第一个证据。这揭示了一种新的内脏外周致敏机制。
Bradykinin (BK) activates sensory nerves and causes hyperalgesia. Transient receptor potential A1 (TRPA1) is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception. TRPA1 can be activated by BK. TRPA1 knockout mice show impaired responses to BK and mechanical nociception. However, direct evidence from sensory nerve terminals is lacking. This study aims to determine the role of TRPA1 in BK-induced visceral mechanical hypersensitivity. Extracellular recordings of action potentials from vagal nodose and jugular neurons are performed in an ex vivo guinea pig esophageal-vagal preparation. Peak frequencies of action potentials of afferent nerves evoked by esophageal distension and chemical perfusion are recorded and compared. BK activates most nodose and all jugular C fibers. This activation is repeatable and associated with a significant increase in response to esophageal distension, which can be prevented by the B2 receptor antagonist WIN64338. TRPA1 agonist allyl isothiocyanate (AITC) activates most BK-positive nodose and jugular C fibers. This is associated with a transient loss of response to mechanical distensions and desensitization to a second AITC perfusion. Desensitization with AITC and pretreatment with TRPA1 inhibitor HC-030031 both inhibit BK-induced mechanical hypersensitivity but do not affect BK-evoked activation in nodose and jugular C fibers. In contrast, esophageal vagal afferent Adelta fibers do not respond to BK or AITC and fail to show mechanical hypersensitivity after BK perfusion. This provides the first evidence directly from visceral sensory afferent nerve terminals that TRPA1 mediates BK-induced mechanical hypersensitivity. This reveals a novel mechanism of visceral peripheral sensitization.