Distribution of vanilloid receptors (VR1) in gastrointestinal tract and their role in mucosal protection mediated by capsaicin-sensitive afferent neurons

香草酸受体（VR1）在胃肠道的分布及其在辣椒素敏感传入神经元介导的粘膜保护中的作用

• 批准号: 14572169
• 负责人: TAKEUCHI Koji
• 金额: $ 2.24万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572169/
• 关键词: Capsaicin-sensitive afferent neuron; capsaicin; vanilloid receptor type 1; gastric protection; EP receptor subtype; bicarbonate secretion; RGM1; cytoprotection

We investigated (1)the role prostaglandins (PGs) and EP receptors play in facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats and mice, (2)the role of VR1 in the HCO_3 secretory response to capsaicin in rat duodenums, in comparison with that induced by mucosal acidification, and (3)the peripheral expression of VR1, in gastric mucosal epithelial cells as well as the role of the receptor in cellular protection, and the following results were obtained ;1.Gastric lesions induced by HCl/ethanol were significantly inhibited by PGE_2 as well as capsaicin. The effect of PGE_2 was antagonized by AE-829 (EP1 antagonist), while the capsaicin action was mitigated by indomethacin as well as sensory deafferentation but not by AE-829. Capsaicin provided a protective action against HCl/ethanol-induced gastric lesions in WT (+/+) mice in an indomethacin-inhibitable manner, and this action was similarly observed in EP1 (-/-) and EP3 (-/-) mice but not in the animals lacking … More IP receptors. Thus, capsaicin exhibits gastric cytoprotection, essentially by stimulating sensory neurons, and this action is facilitated by endogenous PGs through EP2/IP receptors, probably sensitizing the sensory neurons to capsaicin.2.Both capsaicin and acid cause an increase in duodenal HCO_3^-secretion depending on capsaicin-sensitive sensory neuron and mediated by nitric oxide and PGs, yet the mode of their action differs in terms of the ruthenium red-or capsazepine-sensitivity. Although luminal H^+ plays a modulatory role in duodenal HCO_3^-secretion, it is unlikely that the action results from the interaction of H^+ with the ruthenium red-or capsazepine-sensitive site of VR1.3.The distinct expression of VR1 protein and mRNA was detected in RGM-1 as well as the rat stomach and spinal cord. Capsaicin prevented the cell damage induced by ethanol or acid, the effect being abolished by co-addition of capsazepine or ruthenium red. It is assumed that VR1 is expressed peripherally in gastric mucosal epithelial cells and plays a cellular protective role. Less

我们研究了 (1) 前列腺素 (PG) 和 EP 受体在大鼠和小鼠中促进辣椒素对抗 HCl/乙醇的胃保护作用中的作用，(2) 与粘膜酸化诱导的反应相比，VR1 在大鼠十二指肠对辣椒素的 HCO_3 分泌反应中的作用，以及 (3) VR1 的外周表达， 研究人员对胃粘膜上皮细胞以及受体的细胞保护作用进行了研究，得到以下结果：1.PGE_2和辣椒素均能显着抑制HCl/乙醇引起的胃损伤。 PGE_2 的作用被 AE-829（EP1 拮抗剂）拮抗，而辣椒素的作用被吲哚美辛以及感觉传入神经阻滞所减轻，但 AE-829 则没有。辣椒素以吲哚美辛抑制的方式对 WT (+/+) 小鼠中的 HCl/乙醇诱导的胃损伤提供保护作用，这种作用在 EP1 (-/-) 和 EP3 (-/-) 小鼠中也观察到，但在缺乏 IP 受体的动物中没有观察到。因此，辣椒素主要通过刺激感觉神经元表现出胃细胞保护作用，并且这种作用是由内源性 PG 通过 EP2/IP 受体促进的，可能使感觉神经元对辣椒素敏感。2.辣椒素和酸都会导致十二指肠 HCO_3^-分泌增加，具体取决于辣椒素敏感的感觉神经元，并由辣椒素介导 一氧化氮和 PG，但它们的作用方式在钌红或辣椒西平敏感性方面有所不同。尽管管腔H^+在十二指肠HCO_3^-分泌中发挥调节作用，但该作用不太可能是H^+与VR1.3的钌红或辣椒西平敏感位点相互作用的结果。在RGM-1以及大鼠胃和脊髓中检测到VR1蛋白和mRNA的独特表达。辣椒素可防止乙醇或酸引起的细胞损伤，同时添加辣椒素或钌红可消除该作用。推测VR1在胃粘膜上皮细胞外周表达并发挥细胞保护作用。较少的

项目成果

Koji Takeuchi, Shinichi Kato, Yusuke Komoike, Yoshihiro Ogawa, Masanori Takeeda: "Gastric cytoprotection by prostaglandin E2:Relation to EP receptor subtypes. In : Mechanisms and Consequences of Proton Transport,"Urushidani T, Forte JG, Sachs G., Kluwer A

Koji Takeuchi、Shinichi Kato、Yusuke Komoike、Yoshihiro Okawa、Masanori Takeeda：“前列腺素 E2 的胃细胞保护：与 EP 受体亚型的关系。在：质子运输的机制和后果”，Urushidani T、Forte JG、Sachs G.、Kluwer A

Takeuchi K, Hase S, Takeeda M, Nakashima M, Yokota A.: "Prostaglandin EP receptor subtypes and gastric cytoprotection."Inflammopharmacology. 10. 303-312 (2002)

Takeuchi K、Hase S、Takeeda M、Nakashima M、Yokota A.：“前列腺素 EP 受体亚型和胃细胞保护。”炎症药理学。

Kato S, Aihara E, Nakamura A, Hong X, Matsui H, Kohama M, Takeuchi K.: "Expression of vanilloid receptors in rat gastric epithelial cells : Role in cellular protection."Biochemical Pharmacol. 66. 1115-1121 (2003)

Kato S、Aihara E、Nakamura A、Hong X、Matsui H、Kohama M、Takeuchi K.：“大鼠胃上皮细胞中香草素受体的表达：在细胞保护中的作用。”生化药理学。

Onodera S, Nishida K, Takeuchi K.: "Unique profile of lafutidine, a novel histamine H_2-receptor antagonist : mucosal protection throughout gastrointestinal tract mediated by capsaicin-sensitive afferent neurons."Curr Pharm Design on line. (in press).

Onodera S、Nishida K、Takeuchi K.：“拉呋替丁（一种新型组胺 H_2 受体拮抗剂）的独特特征：由辣椒素敏感传入神经元介导的整个胃肠道的粘膜保护。”Curr Pharm Design 在线。

竹内孝治: "NOと胃粘膜"NOと病態"(岡村富夫 編集)"医歯薬出版. 636-640 (2003)

竹内浩二：《NO与胃粘膜》NO与病理学（冈村富夫编辑），石药出版社636-640（2003年）。