P2X3 receptors mediate visceral hypersensitivity during acute chemically-induced colitis and in the post-inflammatory phase via different mechanisms of sensitization.
P2X3 receptors mediate visceral hypersensitivity during acute chemically-induced colitis and in the post-inflammatory phase via different mechanisms of sensitization.
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DOI：
10.1371/journal.pone.0123810
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
De Winter BY
中科院分区：
文献类型：
--
作者：
Deiteren A;van der Linden L;de Wit A;Ceuleers H;Buckinx R;Timmermans JP;Moreels TG;Pelckmans PA;De Man JG;De Winter BY
使用P2X3基因敲除小鼠或更一般的P2X受体拮抗剂进行的实验表明，P2X3受体与内脏超敏有关。我们的目的是研究选择性的P2X3拮抗剂A-317491在生理条件下、急性结肠炎期间和炎症后阶段对内脏敏感性的影响。通过结肠镜监测三硝基苯磺酸结肠炎：在第3天确认结肠炎的存在，然后从第10天开始每隔4天监测一次康复情况，并确定每只大鼠的确切内窥镜愈合时间点。通过量化对照组、急性结肠炎大鼠和结肠炎后大鼠对结直肠扩张的内脏运动反应来评估内脏敏感性。A-317491在内脏敏感性测试前30分钟给药。检测结肠组织和背根神经节中P2X3受体(RT-PCR和免疫组织化学)和细胞内信号分子CDK5、CSK和cASK的表达。用发光法测定结肠扩张对ATP释放的影响。急性结肠炎的大鼠表现出显著的内脏高敏感性，这是剂量依赖的，但不完全被A-317491逆转。感觉过敏伴随着结肠内ATP释放的增加。结肠炎后的大鼠也表现出内脏高敏感性，这种敏感性随剂量的增加而降低，并通过A-317491完全正常化，而不增加三磷酸腺苷的释放。A-317491没有改变对照组的内脏敏感性。对照组、急性结肠炎组和结肠炎后组大鼠结肠和背根神经节中P2X3mRNA和蛋白的表达相似，而CDK5、CSK和CASK在结肠炎后组大鼠结肠中的表达仅在结肠炎后组升高。这些发现表明，在生理条件下，P2X3受体不参与感觉信号的传递，但在急性TNBS结肠炎时，它们调节内脏高敏感性，在炎症后阶段更是如此，尽管其敏化机制不同，证实了P2X3受体是治疗腹痛综合征的潜在新靶点。
Experiments using P2X3 knock-out mice or more general P2X receptor antagonists suggest that P2X3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis. Trinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence. Rats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dose-dependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased release of ATP. A-317491 did not modify visceral sensitivity in controls. P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only. These findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes.
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追求P2X3拮抗剂：用于慢性疼痛和传入敏化的新型治疗学。
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
3.5
作者：
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作者：
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DOI：
10.1073/pnas.252537299
发表时间：
2002-12-24
影响因子：
11.1
作者：
Jarvis, MF;Burgard, EC;Faltynek, C
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Faltynek, C