Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action
Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action
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DOI：
10.1111/j.1476-5381.2010.01063.x
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发表时间：
2011-02-01
影响因子：
7.3
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
--
作者：
Maione, Sabatino;Piscitelli, Fabiana;Di Marzo, Vincenzo
背景技术已知两种非精神活性大麻素，大麻二酚（CBD）和大麻色烯（CBC）在体外调节参与伤害感受机制的蛋白质的活性，包括香草素1型（TRPV 1）和锚蛋白1型（TRPA 1）的瞬时受体电位（TRP）通道、平衡核苷转运蛋白和促进内源性大麻素失活的蛋白质。在这里，我们已经测试了这两种大麻素的活性的下行通路的antinociception.Experimental方法的电活动的ON和OFF神经元的头端腹内侧的延髓在麻醉大鼠被记录在细胞外和甩尾lavelance热刺激进行了测量。将CBD或CBC沿着各种拮抗剂注射到腹外侧中脑导水管周围灰质中。KEY EST-TSCAnabidiol和CBC剂量依赖性地降低麻醉大鼠中ON和OFF神经元的持续活动，同时在甩尾试验中诱导抗伤害性反应。这些作用在3 nmol CBD和6 nmol CBC时最大，并且被大麻素CB 1腺苷A（1）和TRPA 1的选择性拮抗剂拮抗，但不被TRPV 1受体拮抗。CBC和CBD也显著升高了中脑导水管周围灰质腹外侧的内源性大麻素水平。TRPA 1通道的特异性激动剂和内源性大麻素细胞再摄取的合成抑制剂产生类似的CBC和CBD. CONCLUSION和IMPLICATIONSCBD和CBC刺激下行通路的抗伤害感受和镇痛与参与伤害性控制的几个靶蛋白相互作用。这些化合物可能代表具有多种作用机制的有用的治疗剂。
BACKGROUND AND PURPOSETwo non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception.EXPERIMENTAL APPROACHElectrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey.KEY RESULTSCannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB1 adenosine A(1) and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD.CONCLUSIONS AND IMPLICATIONSCBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.