A role for endocannabinoids in indomethacin-induced spinal antinociception
A role for endocannabinoids in indomethacin-induced spinal antinociception
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DOI：
10.1016/s0014-2999(02)02485-8
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发表时间：
2002-11-15
影响因子：
5
通讯作者：
Brune, K
中科院分区：
文献类型：
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作者：
Gühring, H;Hamza, M;Brune, K
d.对三尖杉酯碱合成的抑制不能完全解释非甾体抗炎药诱导的脊髓镇痛作用。在其他介质中，内源性大麻素参与疼痛调节。在脊髓微透析小鼠中进行的福尔马林试验中，吲哚美辛诱导的抗伤害感受可通过大麻素1（CB 1）拮抗剂N-（哌啶-1-基）-5-（4-碘苯基）-1-（2，4-二氯苯基）-4-甲基-1-H-吡唑-3-甲酰胺（AM-251）的共同给药逆转，但不能通过前列腺素E-2的共同输注逆转。消炎痛对CB 1基因敲除小鼠无效。AM-251还逆转了吲哚美辛诱导的抗伤害性感受的炎性痛觉过敏热的测试。此外，在福尔马林试验期间，吲哚美辛降低了脊髓一氧化氮（NO）的水平，这会激活细胞再摄取，从而分解内源性大麻素。NO供体3-甲基-N-亚硝基悉尼酮-5-亚胺（RE-2047）的原伤害感受效应通过共施用内源性大麻素转运体阻断剂N-（4-羟基苯基）花生四烯酸酰胺（AM-404）而消除。此外，AM-251可逆转NO合酶抑制剂N-硝基-L-精氨酸甲酯（L-NAME）的镇痛活性。因此，我们提出，在脊髓水平，吲哚美辛诱导花生四烯酸代谢转向内源性大麻素合成继发于环氧合酶抑制。此外，它降低了NO水平，随后内源性大麻素水平较高。(C)2002 Elsevier Science B. V.保留所有权利。
dInhibition of prostaglandins synthesis does not completely explain non-steroidal anti-inflammatory drug-induced spinal antinociception. Among other mediators, endocannabinoids are involved in pain modulation. Indomethacin-induced antinociception, in the formalin test performed in spinally microdialysed mice, was reversed by co-administration of the cannabinoid 1 (CB1) antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (AM-251), but not by co-infusion of prostaglandin E-2. Indomethacin was ineffective in CB1 knockout mice. AM-251 also reversed the indomethacin-induced antinociception in a test of inflammatory hyperalgesia to heat. Furthermore, during the formalin test, indomethacin lowered the levels of spinal nitric oxide (NO), which activates cellular reuptake and thus breakdown of endocannabinoids. The pronociceptive effect of an NO donor, 3-methyl-N-nitrososydnone-5-imine (RE-2047), was abolished by co-administration of the endocannabinoid transporter blocker N-(4-hydroxyphenyl) arachidonoyl amide (AM-404). Moreover, the antinociceptive activity of the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), was reversed by AM-251. Thus we propose that at the spinal level, indomethacin induces a shift of arachidonic acid metabolism towards endocannabinoids synthesis secondary to cyclooxygenase inhibition. In addition, it lowers NO levels with subsequent higher levels of endocannabinoids. (C) 2002 Elsevier Science B.V. All rights reserved.