Physiological evidence of a postsynaptic inhibition of the tail flick reflex by a cannabinoid receptor agonist
Physiological evidence of a postsynaptic inhibition of the tail flick reflex by a cannabinoid receptor agonist
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DOI：
10.1016/j.ejphar.2008.10.061
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发表时间：
2009-01-05
影响因子：
5
通讯作者：
Henry, James L.
中科院分区：
文献类型：
--
作者：
Dableh, Liliane J.;Yashpal, Kiran;Henry, James L.
目前的证据表明，大麻素具有抗伤害性，这种作用在一定程度上是由脊髓机制介导的。解剖学研究已将大麻素CB1受体定位于脊髓内突触前和突触后的位置。然而，行为测试并没有明确指出这些网站的相对重要性。本研究采用甩尾实验作为大鼠急性疼痛模型，以确定合成大麻素受体激动剂Win 55,212-2((R)-(+)-[2，3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrolo[1，2，3-de]-1，4-benzoxazinyl]-(1-naphthalenyl)methanone的作用部位。Win 55,212-2(3 mg/kg，ip)延长了从有害辐射热源撤尾的潜伏期，表明它在该模型中具有抗伤害性。使用相同的范式，然后测试Win 55,212-2对抗突触诱导的伤害性超敏反应对尾部伤害性热刺激(热水浸泡尾巴)的反应。Win 55,212-2阻断了这种过敏反应，证实了大麻素受体激动剂的脊髓作用部位。此外，Win 55,212-2阻断了鞘内注射P物质引起的伤害性超敏反应。由于P物质作用于脊髓背角突触后速激肽NK1受体，这些数据被解释为Win 55,212-2至少部分地通过突触后作用部位表达其抗超敏作用；该数据不排除突触前作用部位。这项研究表明，大麻素可能通过脊髓中突触后的作用部位诱导镇痛，以及它们可能与P物质信号相互作用。(C)2008爱思唯尔B.V.保留所有权利。
Current evidence indicates that cannabinoids are antinociceptive and this effect is in part mediated by spinal mechanisms. Anatomical studies have localized cannabinoid CB1 receptors to pre- and postsynaptic sites within the spinal cord. However, behavioural tests have not clearly indicated the relative importance of each of these sites. In this study, the tail flick test was used as a model of acute pain in the rat to determine the site of action of WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), a synthetic cannabinoid receptor agonist. WIN 55,212-2 (3 mg/kg, i.p.) increased the latency of tail withdrawal from a noxious radiant heat source, indicating it is antinociceptive in this model. Using the same paradigm, WIN 55,212-2 was then tested against the synaptically-induced nociceptive hypersensitivity in response to noxious thermal stimulation of the tail (hot water tail immersion). WIN 55,212-2 blocked this hypersensitivity, confirming a spinal site of action of the cannabinoid receptor agonist. Further, WIN 55,212-2 blocked the nociceptive hypersensitivity induced by intrathecal administration of substance P. As substance P acts on postsynaptic tachykinin NK1 receptors in the dorsal horn of the spinal cord, the data are interpreted to suggest that WIN 55,212-2 expressed its anti-hypersensitivity effects at least partially via a postsynaptic site of action; the data do not rule out a presynaptic site of action. This study suggests that cannabinoids may induce analgesia via a postsynaptic site of action in the spinal cord, as well as the possibility that they may interact with substance P signaling. (C) 2008 Elsevier B.V. All rights reserved.