Dinis Paulo, Charrua Ana, Avelino Antonio, Yaqoob Mohammed, Bevan Stuart, Nagy Istvan, Cruz Francisco
Institute of Histology and Embryology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
J Neurosci. 2004 Dec 15;24(50):11253-63. doi: 10.1523/JNEUROSCI.2657-04.2004.
The role of anandamide in the development of inflammatory hyperalgesia and visceral hyperreflexia was studied in the rat urinary bladder. Animals were given intraperitoneal cyclophosphamide injection, which evokes painful hemorrhagic cystitis accompanied by increased bladder reflex activity. The vanilloid receptor 1 [transient receptor potential vanilloid 1 (TRPV1)] antagonist capsazepine, applied onto the serosal surface of bladders, significantly reduced the hyperreflexia. Mass spectrometric analysis revealed that cyclophosphamide injection significantly and persistently increased the anandamide content of bladder tissues. The increase in the anandamide content paralleled the development of reflex hyperactivity. Anandamide (1-100 microm), applied onto the serosal surface of naive bladders, increased the reflex activity in a concentration-dependent manner. Repeated anandamide applications did not produce desensitization of the response. The anandamide-evoked effect was blocked by capsazepine or by instillation of resiniferatoxin, the ultrapotent TRPV1 agonist, into the bladders 24 hr before the anandamide challenge. The cannabinoid 1 receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] significantly increased the potency of anandamide in enhancing bladder reflex activity in naive but not in cyclophosphamide-injected animals. Application of the fatty acid amide hydrolyze inhibitor palmitoylisopropylamine onto the serosal surface of bladders also increased the reflex activity both in naive and cyclophosphamide-injected rats. This latter effect in naive animals was blocked by capsazepine and by resiniferatoxin pretreatment. Finally, intravesical instillation of anandamide (50 microm) increased c-fos expression in the spinal cord, which was reduced by capsazepine or by resiniferatoxin pretreatment. These results suggest that anandamide, through activating TRPV1, contributes to the development of hyperreflexia and hyperalgesia during cystitis.
在大鼠膀胱中研究了花生四烯乙醇胺在炎性痛觉过敏和内脏反射亢进发展过程中的作用。给动物腹腔注射环磷酰胺，这会引发伴有膀胱反射活动增强的疼痛性出血性膀胱炎。将香草酸受体1 [瞬时受体电位香草酸亚型1 (TRPV1)] 拮抗剂辣椒素应用于膀胱浆膜表面，可显著降低反射亢进。质谱分析显示，注射环磷酰胺可显著且持续增加膀胱组织中花生四烯乙醇胺的含量。花生四烯乙醇胺含量的增加与反射活动亢进的发展平行。将花生四烯乙醇胺 (1 - 100微摩尔) 应用于未处理膀胱的浆膜表面，可呈浓度依赖性增加反射活动。重复应用花生四烯乙醇胺不会使反应脱敏。在给予花生四烯乙醇胺刺激前24小时，向膀胱内注入辣椒素或超效TRPV1激动剂树脂毒素可阻断花生四烯乙醇胺诱发的效应。大麻素1受体拮抗剂SR141716A [N - 哌啶基 - 5 - (4 - 氯苯基) - 1 - (2,4 - 二氯苯基) - 4 - 甲基吡唑 - 3 - 甲酰胺] 可显著增强花生四烯乙醇胺在未处理动物中增强膀胱反射活动的效力，但在注射环磷酰胺的动物中无效。将脂肪酸酰胺水解酶抑制剂棕榈酰异丙胺应用于膀胱浆膜表面，在未处理和注射环磷酰胺的大鼠中均可增加反射活动。在未处理动物中，后一种效应可被辣椒素和树脂毒素预处理阻断。最后，膀胱内注入花生四烯乙醇胺 (50微摩尔) 可增加脊髓中c - fos的表达，而辣椒素或树脂毒素预处理可降低这种表达。这些结果表明，花生四烯乙醇胺通过激活TRPV1，在膀胱炎期间促进反射亢进和痛觉过敏的发展。
