Arvanil-induced inhibition of spasticity and persistent pain:: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB1/CB2 receptors
Arvanil-induced inhibition of spasticity and persistent pain:: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB1/CB2 receptors
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DOI：
10.1016/s0014-2999(02)01369-9
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发表时间：
2002-03-29
影响因子：
5
通讯作者：
Baker, D
中科院分区：
文献类型：
--
作者：
Brooks, JW;Pryce, G;Baker, D
在多发性硬化症小鼠模型中，大麻素受体的激活引起痉挛的抑制，在大鼠福尔马林试验中引起持续性疼痛的抑制。内源性大麻素anandamide抑制痉挛和持续性疼痛。它不仅与大麻素受体结合，而且也是I型香草素受体（VR 1）的完全激动剂。我们发现香草酸VR 1受体激动剂（辣椒素和N-N '-（3-甲氧基-4-氨基乙氧基-苄基）-（4-叔丁基-苄基）-脲[SDZ-249-665]）表现出小的但显著的痉挛抑制作用，其可被香草素VR 1受体拮抗剂辣椒平、Arvanil（辣椒素和大麻素之间的结构“杂合物”）在剂量（例如0.01 mg/kg i. v.）其中辣椒素和大麻素CB 1受体激动剂无效。在大麻素CB 1受体基因缺陷小鼠或在大麻素和香草素受体拮抗剂存在下的野生型小鼠中，arvanil的抗痉挛作用不变。同样，arvanil（0.1-0.25 mg/kg）在福尔马林试验中表现出有效的镇痛作用，大麻素和香草素受体拮抗剂不能逆转该作用。这些发现表明，通过arvanil激活不同于大麻素CB 1/CB 2受体和香草素VR 1受体的作用位点导致可能在治疗上被利用的抗痉挛/镇痛作用。(C)2002 Elsevier Science B. V.保留所有权利。
Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type I (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine, Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB1 receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB1 receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB1/CB2 receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically. (C) 2002 Elsevier Science B.V. All rights reserved.