TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis.
TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis.
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DOI：
10.1016/j.pain.2014.03.023
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发表时间：
2014-07
期刊：
影响因子：
7.4
通讯作者：
Davis BM
中科院分区：
文献类型：
--
作者：
DeBerry JJ;Schwartz ES;Davis BM
膀胱疼痛是间质性膀胱炎/膀胱疼痛综合征的主要症状。我们采用全身注射环磷酰胺（CYP），一种烷基化抗肿瘤药物，来诱导膀胱炎，并检查两个通道的作用，这两个通道先前被证明是炎症性内脏痛感过敏所必需的：瞬时受体电位香兰素-1 （TRPV1）和锚蛋白-1 （TRPA1）。每隔一天注射CYP （100 mg/kg，每日1次），连续5天，伴膀胱水肿和尿路上皮溃疡，但未见明显血浆外渗和中性粒细胞浸润。甲苯胺蓝染色显示CYP治疗后脱颗粒膀胱肥大细胞数量显著增加。尽管有这种轻微的病理，cypp治疗的小鼠在最后一次注射后的一天表现出膀胱痛觉过敏，持续7天。尽管许多先前的内脏痛觉过敏研究报道了背根神经节神经元TRPV1表达和/或功能的变化，但我们发现膀胱传入神经TRPV1表达或敏感性没有变化，这是基于膀胱传入神经对辣椒素反应的百分比，包括在亚最大浓度下。相比之下，表达功能性TRPA1蛋白的膀胱传入神经（即对芥菜油有反应的膀胱传入神经）的百分比在CYP治疗1天后增加了~2.5倍，并在7天后保持显著升高。此外，膀胱痛觉过敏可以通过TRPA1拮抗剂HC-030031 （300 mg/kg, ig）的急性治疗得到逆转。我们的研究结果表明，cypp诱导的膀胱痛觉过敏可以在没有强烈炎症或原发性传入TRPV1改变的情况下诱导。然而，TRPA1的表达发生了显著变化，阻断TRPA1可减轻cypp诱导的膀胱痛觉过敏。
Urinary bladder pain is a primary symptom associated with interstitial cystitis/painful bladder syndrome. We employed systemic injections of cyclophosphamide (CYP), an alkylating anti-neoplastic agent, to induce cystitis and examine the roles of two channels previously shown to be required for inflammatory visceral hyperalgesia: transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1). Injection of CYP (100 mg/kg, i.p.) every other day for five days was accompanied by bladder edema and urothelial ulceration, but without significant plasma extravasation or infiltration of neutrophils. Toluidine blue staining showed a significant increase in the number of degranulated bladder mast cells following CYP treatment. Despite this mild pathology, CYP-treated mice exhibited bladder hyperalgesia one day following the final injection that persisted seven days later. Although many previous studies of visceral hyperalgesia have reported changes in dorsal root ganglion neuron TRPV1 expression and/or function, we found no change in bladder afferent TRPV1 expression or sensitivity, based on the percentage of bladder afferents responsive to capsaicin, including at sub-maximal concentrations. In contrast, the percentage of bladder afferents expressing functional TRPA1 protein (i.e., those responsive to mustard oil) increased ~2.5-fold one day after CYP treatment, and remained significantly elevated seven days later. Moreover, bladder hyperalgesia was reversed by acute treatment with the TRPA1 antagonist, HC-030031 (300 mg/kg, i.p.). Our results indicate that CYP-induced bladder hyperalgesia can be induced without robust inflammation or changes in primary afferent TRPV1. However, significant changes were seen in TRPA1 expression, and blockade of TRPA1 alleviated CYP-induced bladder hyperalgesia.
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