Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Br J Pharmacol. 2009 Aug;157(8):1494-501. doi: 10.1111/j.1476-5381.2009.00312.x.
The effects of centrally administered cannabinoids on body core temperature (Tc) and the contribution of endogenous cannabinoids to thermoregulation and fever induced by lipopolysaccharide (LPS) (Sigma Chem. Co., St. Louis, MO, USA) were investigated.
Drug-induced changes in Tc of male Wistar rats were recorded over 6 h using a thermistor probe (Yellow Springs Instruments 402, Dayton, OH, USA) inserted into the rectum.
Injection of anandamide [(arachidonoylethanolamide (AEA); Tocris, Ellisville, MO, USA], 0.01-1 microg i.c.v. or 0.1-100 ng intra-hypothalamic (i.h.), induced graded increases in Tc (peaks 1.5 and 1.6 degrees C at 4 h after 1 microg i.c.v. or 10 ng i.h.). The effect of AEA (1 microg, i.c.v.) was preceded by decreases in tail skin temperature and heat loss index (values at 1.5 h: vehicle 0.62, AEA 0.48). Bell-shaped curves were obtained for the increase in Tc induced by the fatty acid amide hydrolase inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (Cayman Chemical Co., Ann Arbor, MI, USA) (0.001-1 ng i.c.v.; peak 1.9 degrees C at 5 h after 0.1 ng) and arachidonyl-2-chloroethylamide (ACEA; Tocris) (selective CB(1) agonist; 0.001-1 microg i.c.v.; peak 1.4 degrees C 5 h after 0.01 microg), but (R,S)-(+)-(2-Iodo-5-nitrobenzoyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indole-3-yl] methanone (Tocris) (selective CB(2) agonist) had no effect on Tc. AEA-induced fever was unaffected by i.c.v. pretreatment with 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl) methanone (Tocris) (selective CB(2) antagonist), but reduced by i.c.v. pretreatment with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; Tocris) (selective CB(1) antagonist). AM251 also reduced the fever induced by ACEA or LPS.
The endogenous cannabinoid AEA induces an integrated febrile response through activation of CB(1) receptors. Endocannabinoids participate in the development of the febrile response to LPS constituting a target for antipyretic therapy.
研究了中枢给予大麻素对核心体温（Tc）的影响，以及内源性大麻素对脂多糖（LPS）（Sigma Chem. Co.，圣路易斯，密苏里州，美国）引起的体温调节和发热的贡献。
使用插入直肠的热敏电阻探头（Yellow Springs Instruments 402，代顿，俄亥俄州，美国）记录雄性 Wistar 大鼠在 6 小时内的 Tc 药物诱导变化。
阿纳达酰胺（[花生四烯酰乙醇胺（AEA）；Tocris，埃利斯维尔，密苏里州，美国]，0.01-1μg i.c.v. 或 0.1-100ng 下丘脑内（i.h.），诱导 Tc 呈梯度增加（在 1μg i.c.v. 或 10ng i.h. 后 4 小时达到 1.5 和 1.6°C 的峰值）。AEA（1μg，i.c.v.）的作用之前，尾巴皮肤温度和热损失指数降低（在 1.5 小时时的值：载体 0.62，AEA 0.48）。通过脂肪酸酰胺水解酶抑制剂[3-（3-氨甲酰基苯基）苯基] N-环己基氨基甲酸酯（Cayman Chemical Co.，安阿伯，密歇根州，美国）（0.001-1ng i.c.v.；在 0.1ng 后 5 小时达到 1.9°C 的峰值）和花生四烯酰基-2-氯乙基酰胺（AEA；Tocris）（选择性 CB（1）激动剂；0.001-1μg i.c.v.；在 0.01μg 后 5 小时达到 1.4°C 的峰值），获得了 Tc 诱导的增加的钟形曲线，但（R，S）-（+）-（2-碘-5-硝基苯甲酰基）-[1-（1-甲基-哌啶-2-基甲基）-1H-吲哚-3-基]甲酮（Tocris）（选择性 CB（2）激动剂）对 Tc 没有影响。AEA 诱导的发热不受 i.c.v.预处理 6-碘-2-甲基-1-[2-（4-吗啉基）乙基]-1H-吲哚-3-基]（4-甲氧基苯基）甲酮（Tocris）（选择性 CB（2）拮抗剂）的影响，但通过 i.c.v.预处理 N-（哌啶-1-基）-5-（4-碘苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-羧酰胺（AM251；Tocris）（选择性 CB（1）拮抗剂）减少。AM251 还降低了 ACEA 或 LPS 引起的发热。
内源性大麻素 AEA 通过激活 CB（1）受体诱导综合发热反应。内源性大麻素参与 LPS 引起的发热反应的发展，构成退热治疗的靶点。
