Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia
Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia
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DOI：
10.1152/ajpgi.00002.2008
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发表时间：
2008-05-01
影响因子：
4.5
通讯作者：
Bunnett, Nigel W.
中科院分区：
文献类型：
--
作者：
Sipe, Walter E. B.;Brierley, Stuart M.;Bunnett, Nigel W.
瞬时受体电位香草酸 4 介导蛋白酶激活受体 2 诱导的结肠传入神经敏化和内脏痛觉过敏。 Am J Physiol Gastrointest Liver Physiol 294：G1288-G1298，2008。首次发表于 2008 年 3 月 6 日；doi：10.1152/ajpgi.00002.2008。-蛋白酶激活受体 (PAR(2)) 由伤害性神经元表达，并在炎症过程中被来自肥大细胞、肠腔和肠壁的蛋白酶激活。流通。 PAR2 激动剂通过未知机制引起肠道感觉神经元过度兴奋和对扩张刺激的痛觉过敏。我们评估了瞬时受体电位香草酸 4 (TRPV4) 在 PAR(2) 诱导的小鼠结肠机械痛觉过敏中的作用。通过逆行追踪鉴定的结肠感觉神经元表达免疫反应性 TRPV4、PAR(2) 和降钙素基因相关肽，因此与伤害感受有关。为了评估伤害感受，通过腹部肌肉肌电图测量内脏运动反应（VMR）对结直肠扩张（CRD）的影响。在 TRPV4 (+/+) 小鼠中，管腔内 PAR(2) 激活肽 (PAR(2)-AP) 在 6-24 小时内将 VMR 加剧至分级 CRD，表明机械性痛觉过敏。 TRPV4 (-/-) 小鼠中未观察到 PAR(2) 诱导的痛觉过敏。 PAR(2)-AP 引起 TRPV4 (+/+) 小鼠结肠传入神经元动作电位放电，但不引起 TRPV4(-/-) 小鼠动作电位放电。 TRPV4 激动剂 5', 6'- 环氧二十碳三烯酸和 4 α-佛波醇 12,13-二癸酸酯刺激结肠传入纤维中动作电位的放电，并增强从逆行标记的结肠背根神经节神经元记录的电流反应，证实了功能性 TRPV4 的表达。 PAR(2)-AP 增强了这些反应，表明 TRPV4 致敏。因此TRPV4由支配结肠的初级脊髓传入神经元表达。 PAR(2) 的激活会增加这些神经元中的电流，引起结肠传入纤维动作电位的放电，并诱发机械性痛觉过敏。这些反应需要功能性 TRPV4 的存在。因此，TRPV4 是 PAR(2) 诱导的机械痛觉过敏和结肠传入神经元兴奋所必需的。
Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol 294: G1288-G1298, 2008. First published March 6, 2008;doi:10.1152/ajpgi.00002.2008.-Protease- activated receptor (PAR(2)) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 ( TRPV4) in PAR(2)-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR(2), and calcitonin generelated peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4 (+/+) mice, intraluminal PAR(2) activating peptide ( PAR(2)-AP) exacerbated VMR to graded CRD from 6-24 h, indicative of mechanical hyperalgesia. PAR(2)-induced hyperalgesia was not observed in TRPV4 (-/-) mice. PAR(2)-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4 (+/+) mice, but not from TRPV4(-/-) mice. The TRPV4 agonists 5', 6'- epoxyeicosatrienoic acid and 4 alpha-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR(2)-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR(2) increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR(2)-induced mechanical hyperalgesia and excitation of colonic afferent neurons.