Suppression of adenosine A2a receptors alleviates bladder overactivity and hyperalgesia in cyclophosphamide-induced cystitis by inhibiting TRPV1
Suppression of adenosine A2a receptors alleviates bladder overactivity and hyperalgesia in cyclophosphamide-induced cystitis by inhibiting TRPV1
复制标题
抑制腺苷 A(2a) 受体可通过抑制 TRPV1 减轻环磷酰胺诱发的膀胱炎中的膀胱过度活动和痛觉过敏。
DOI：
10.1016/j.bcp.2020.114340
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发表时间：
2021-01-01
影响因子：
5.8
通讯作者：
Li，Longkun
中科院分区：
文献类型：
--
作者：
Yang，Yang;Zhang，Hengshuai;Li，Longkun
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种慢性膀胱炎症，其特征是排尿频率增加、尿急和盆腔疼痛。膀胱传入神经的敏感化被广泛认为是IC/BPS发生的病理生理变化之一。有证据表明，腺苷A2 a受体参与调节感觉传入的敏化。然而，腺苷A2 a受体对膀胱炎的作用仍不清楚。本研究采用环磷酰胺腹腔注射建立大鼠慢性膀胱炎模型。通过膀胱测压和行为学测试来研究膀胱排尿功能和伤害性疼痛。慢性膀胱炎大鼠表现出膀胱过度活动的症状，其特征在于膀胱排尿频率和排尿压力增加。结果表明，A2 a受体在膀胱传入纤维和背根神经节（DRG）神经元中的表达明显增加。A2 a受体拮抗剂ZM 241385可预防CYP诱导的膀胱炎引起的膀胱过度活动和痛觉过敏。此外，A2 a受体和TRPV 1在DRG神经元上共表达。TRPV 1拮抗剂辣椒平阻断A2 a受体激动剂CGS 21680诱导的膀胱过度活动。与此相反，ZM 241385显着抑制辣椒素诱导的DRG神经元细胞内钙浓度的增加。这些结果表明，抑制膀胱传入纤维中的腺苷A2 a受体可通过抑制TRPV 1减轻CYP诱导的大鼠膀胱炎引起的膀胱过度活动和痛觉过敏，表明膀胱传入纤维中的腺苷A2 a受体是治疗IC/BPS的潜在治疗靶点。
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a type of chronic bladder inflammation characterized by increased voiding frequency, urgency and pelvic pain. The sensitization of bladder afferents is widely regarded as one of the pathophysiological changes in the development of IC/BPS. There is evidence that adenosine A2areceptors are involved in regulating the sensitization of sensory afferents. However, the effect of adenosine A2areceptors on cystitis remains unknown. In the present study, a rat model of chronic cystitis was established by intraperitoneal injection with cyclophosphamide (CYP). Cystometry and behavioral tests were performed to investigate bladder micturition function and nociceptive pain. The rats with chronic cystitis showed symptoms of bladder overactivity, characterized by an increase in bladder voiding frequency and voiding pressure. CYP treatment significantly increased the expression of the A2areceptor in bladder afferent fibers and dorsal root ganglion (DRG) neurons. The A2areceptor antagonist ZM241385 prevented bladder overactivity and hyperalgesia elicited by CYP-induced cystitis. In addition, the A2areceptor and TRPV1 were coexpressed on DRG neurons. The TRPV1 antagonist capsazepine blocked bladder overactivity induced by the A2areceptor agonist CGS21680. In contrast, ZM241385 significantly inhibited the capsaicin-induced increase in intracellular calcium concentration in DRG neurons. These results suggest that suppression of adenosine A2areceptors in bladder afferents alleviates bladder overactivity and hyperalgesia elicited by CYP-induced cystitis in rats by inhibiting TRPV1, indicating that the adenosine A2areceptor in bladder afferents is a potential therapeutic target for the treatment of IC/BPS.