Fatty acid binding protein deletion suppresses inflammatory pain through endocannabinoid/N-acylethanolamine-dependent mechanisms.
Fatty acid binding protein deletion suppresses inflammatory pain through endocannabinoid/N-acylethanolamine-dependent mechanisms.
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DOI：
10.1186/s12990-015-0056-8
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发表时间：
2015-08-28
期刊：
影响因子：
3.3
通讯作者：
Thanos PK
中科院分区：
文献类型：
--
作者：
Kaczocha M;Glaser ST;Maher T;Clavin B;Hamilton J;O'Rourke J;Rebecchi M;Puopolo M;Owada Y;Thanos PK
脂肪酸结合蛋白（FABP）作为细胞内载体，将内源性大麻素和N-酰基乙醇胺递送至其分解代谢酶。FABP的抑制减少了内源性大麻素的转运和细胞中的catalysts，FABP抑制剂在小鼠中产生抗伤害感受和抗炎作用。然而，在缺乏FABP的小鼠中的潜在镇痛作用尚未进行测试。缺乏对内源性大麻素表现出最高亲和力的FABP 5和FABP 7的小鼠具有升高水平的内源性大麻素anandamide和相关的N-酰基乙醇胺棕榈酰乙醇酰胺和油酰乙醇酰胺。在FABP 5/7基因敲除小鼠的大脑中，其他FABPs或内源性大麻素相关蛋白的表达没有代偿性变化。这些小鼠在炎性和内脏痛的角叉菜胶、福尔马林和乙酸试验中表现出降低的伤害感受。FABP 5/7基因敲除小鼠的抗伤害效应通过以特定方式用大麻素受体1、过氧化物酶体增殖物激活受体α和瞬时受体电位香草素1受体拮抗剂预处理而逆转。最后，基因敲除小鼠没有运动障碍。这项研究表明，缺乏FABPs的小鼠具有升高的N-酰基乙醇胺水平，这与FABPs在体内调节内源性大麻素和N-酰基乙醇胺张力的想法一致。在基因敲除小鼠中观察到的抗伤害感受作用支持FABP在调节伤害感受中的作用，并表明这些蛋白质应作为未来镇痛药开发的靶点。
Fatty acid binding proteins (FABPs) serve as intracellular carriers that deliver endocannabinoids and N-acylethanolamines to their catabolic enzymes. Inhibition of FABPs reduces endocannabinoid transport and catabolism in cells and FABP inhibitors produce antinociceptive and anti-inflammatory effects in mice. Potential analgesic effects in mice lacking FABPs, however, have not been tested. Mice lacking FABP5 and FABP7, which exhibit highest affinities for endocannabinoids, possessed elevated levels of the endocannabinoid anandamide and the related N-acylethanolamines palmitoylethanolamide and oleoylethanolamide. There were no compensatory changes in the expression of other FABPs or in endocannabinoid-related proteins in the brains of FABP5/7 knockout mice. These mice exhibited reduced nociception in the carrageenan, formalin, and acetic acid tests of inflammatory and visceral pain. The antinociceptive effects in FABP5/7 knockout mice were reversed by pretreatment with cannabinoid receptor 1, peroxisome proliferator-activated receptor alpha, and transient receptor potential vanilloid 1 receptor antagonists in a modality specific manner. Lastly, the knockout mice did not possess motor impairments. This study demonstrates that mice lacking FABPs possess elevated levels of N-acylethanolamines, consistent with the idea that FABPs regulate the endocannabinoid and N-acylethanolamine tone in vivo. The antinociceptive effects observed in the knockout mice support a role for FABPs in regulating nociception and suggest that these proteins should serve as targets for the development of future analgesics.