Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative
Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative
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DOI：
10.1016/j.pnpbp.2017.07.012
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发表时间：
2017-10
影响因子：
5.6
通讯作者：
N. Silva;F. Gomes;Miriam D. Fonseca;R. Mechoulam;A. Breuer;T. Cunha;F. Guimarães
中科院分区：
文献类型：
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作者：
N. Silva;F. Gomes;Miriam D. Fonseca;R. Mechoulam;A. Breuer;T. Cunha;F. Guimarães
大麻二酚（CBD）是一种植物大麻素，具有多种药理作用和几种潜在的治疗特性。然而，其低口服生物利用度可能限制其临床应用。初步结果表明，CBD分子的降解增加了其药理学效力。在这里，我们研究了氟化CBD类似物HUF-101（3，10和30 mg/kg）是否会诱导抗伤害作用。将HUF-101的作用与CBD（10、30和90 mg/kg）和大麻素CB 1/2受体激动剂WIN 55、212-2（1、3和5 mg/kg）诱导的作用进行比较。这些药物在雄性瑞士小鼠中进行了测试，这些小鼠接受了以下预测抗伤害性药物的模型：热板、乙酸诱导的扭体和角叉菜胶诱导的炎性痛觉过敏。为了评估CB 1和CB 2受体在HUF-101和CBD效应中的参与，小鼠在HUF-101、CBD或WIN 55，212-2之前30分钟接受CB 1受体拮抗剂AM 251（1或3 mg/kg）或CB 2受体拮抗剂AM 630（1或3 mg/kg）。在热板试验中，HUF-101（30 mg/kg）和WIN 55，212-2（5 mg/kg）诱导抗伤害性感受作用，其通过用AM 251和AM 630预处理而减弱。在腹部扭体试验中，CBD（30和90 mg/kg）、HUF-101（30 mg/kg）和WIN 55，212-2（3和5 mg/kg）诱导抗伤害感受作用，其通过扭体次数的减少来指示。然而，在该试验中，用AM 630预处理不减轻任何药物诱导的作用，而用AM 251预处理减弱了由WIN 55，212-2引起的作用。在角叉菜胶诱导的痛觉过敏试验中，CBD（30和90 mg/kg）、HUF-101（3、10和30 mg/kg）和WIN 55，212-2（1 mg/kg）降低了通过电子von Frey方法测量的机械痛觉过敏的强度。AM 251和AM 630的预处理减弱了所有化合物的作用。此外，我们评估了HUF-101是否会诱导经典的大麻素CB 1受体介导的四分体（运动不足、僵住、体温过低和抗伤害感受）。与WIN 55，212-2不同，CBD和HUF-101不诱导大麻素四分体。这些发现表明，HUF-101在比CBD更低的剂量下产生抗伤害作用，表明添加氟化物改善了其药理学特征。此外，CBD和HUF-101的一些抗伤害效应似乎涉及CB 1和CB 2受体的激活。
Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30 mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90 mg/kg) and the cannabinoid CB1/2receptor agonist WIN55,212-2 (1, 3, and 5 mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid-induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB1and CB2receptors in HUF-101 and CBD effects, mice received the CB1receptor antagonist AM251 (1 or 3 mg/kg) or the CB2receptor antagonist AM630 (1 or 3 mg/kg) 30 min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30 mg/kg) and WIN55,212-2 (5 mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90 mg/kg), HUF-101 (30 mg/kg), and WIN55,212-2 (3 and 5 mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90 mg/kg), HUF-101 (3, 10 and 30 mg/kg) and WIN55,212-2 (1 mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF-101 would induce the classic cannabinoid CB1receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212-2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB1and CB2receptors.