Department of Pharmacology, Institute of Biological Sciences, ICB-UFMG, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, CEP 31.270-100, Brazil.
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, via Campi Flegrei, 34, Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy.
Pharmacol Rep. 2020 Feb;72(1):96-103. doi: 10.1007/s43440-019-00053-6. Epub 2020 Jan 10.
Xylazine is an α adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine.
The rat paw pressure test, in which hyperalgesia was induced by the intraplantar injection of prostaglandin E, was performed.
Xylazine administered via an intraplantar injection (25, 50 and 100 μg) induced a peripheral antinociceptive effect against prostaglandin E (2 μg)-induced hyperalgesia. This effect was blocked by treatment with the selective CB cannabinoid antagonist AM251 (20, 40 and 80 μg) but not by the selective CB cannabinoid antagonist AM630 (100 μg). The anandamide reuptake inhibitor VDM11 (2.5 μg) intensified the peripheral antinociceptive effect of a submaximal dose of xylazine (25 μg), and the inhibitor of endocannabinoid enzymatic hydrolysis, MAFP (0.5 μg), showed a tendency towards this same effect. In addition, liquid-chromatography mass spectrometric analysis indicated that xylazine (100 μg) treatment was associated with an increase in anandamide levels in the rat paws treated with PGE.
The present results provides evidence that the peripheral antinociceptive effect of the α adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB cannabinoid receptor activation.
可乐定是一种广泛用于兽医和动物实验程序的α肾上腺素能受体激动剂，可产生镇痛、镇静和肌肉松弛作用，而不会引起全身麻醉。考虑到可乐定诱导的外周镇痛作用的机制以及肾上腺素能和内源性大麻素系统之间潜在的相互作用知之甚少，本研究探讨了后者系统在可乐定机制中的贡献。
进行了大鼠足底压力测试，其中通过足底内注射前列腺素 E 诱导痛觉过敏。
通过足底内注射（25、50 和 100μg）给予可乐定可诱导对前列腺素 E（2μg）诱导的痛觉过敏的外周镇痛作用。这种作用被选择性 CB 大麻素拮抗剂 AM251（20、40 和 80μg）阻断，但不是被选择性 CB 大麻素拮抗剂 AM630（100μg）阻断。大麻素再摄取抑制剂 VDM11（2.5μg）增强了可乐定（25μg）的亚最大剂量的外周镇痛作用，内源性大麻素酶水解抑制剂 MAFP（0.5μg）也表现出这种趋势。此外，液相色谱-质谱分析表明，可乐定（100μg）处理与用 PGE 处理的大鼠足中花生四烯酸水平的增加相关。
本研究结果提供了证据表明，α肾上腺素能受体激动剂可乐定的外周镇痛作用可能是由于花生四烯酸的释放和随后的 CB 大麻素受体激活所致。
