Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin
Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin
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DOI：
10.1016/j.npep.2011.03.005
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发表时间：
2011-06-01
期刊：
影响因子：
2.9
通讯作者：
Reeh, Peter W.
中科院分区：
文献类型：
--
作者：
Engel, Matthias A.;Izydorczyk, Iwona;Reeh, Peter W.
大麻素诱导的抗伤害感受依赖于外周和中枢神经系统中抑制性大麻素受体（CB 1）的激活。然而，大多数大麻素在较高浓度下也激活与CB 1共表达的兴奋性离子型瞬时受体电位（TRP）通道，这些通道在激活时含有并释放降钙素基因相关肽（CGRP）。在宽的浓度范围（0.01-100 μ M）内，我们研究了内源性大麻素anandamide和植物衍生的Delta（9）-THC的分子作用原理，这些物质可用于镇痛。分离的大鼠和小鼠皮肤制备物用于测量由有害热（47 ℃）和辣椒素（0.5 μ M）诱导的CGRP释放，已知刺激物激活辣椒素受体TRPV 1。在低浓度（0.1 μ M）下，两种大麻素均抑制刺激的CGRP释放34- 65%，在AM 251的CBI阻断下以及在整体CB 1但不是TRPV 1敲除小鼠中不存在这种作用。在高浓度（100 μ M）大麻素引起CGRP释放本身和脱敏随后的热反应，其效果是不存在下TRPV 1阻断BCTC和全球TRPV 1，但不是CBI敲除。较低（0.01 μ M）和中间浓度（1和10 μ M）的大麻素是无效的。CB 1（-/-）中的兴奋和脱敏作用没有更多表达（去抑制），TRPV 1（-/-）中的抑制作用没有更强。非特异性去极化（KCl）诱导的CGRP释放不受大麻素的调节。一个偶然的发现是，整体CB 1（-/-）显示出降低的热敏感性，几乎与TRPV 1（-/-）一样低，并且与它们的行为表型雅阁。总之，外周作用CB 1激动剂的抗伤害感受效力不受TRPV 1的相反刺激作用的抑制，而是受其自身有限的功效和狭窄的浓度-反应关系的抑制。(C)2011爱思唯尔有限公司保留所有权利。
Cannabinoid-induced antinociception relies on activation of inhibitory cannabinoid receptors (CB1) in the peripheral and central nervous system. However, most cannabinoids at higher concentration also activate excitatory ionotropic transient receptor potential (TRP) channels coexpressed with CB1 in primary nociceptive neurons that contain and release calcitonin gene-related peptide (CGRP) upon activation. Over a wide concentration range (0.01-100 mu M) we investigated the molecular action principles of the endocannabinoid anandamide and of the plant-derived Delta(9)-THC that can be prescribed for analgesia. Isolated rat and mouse skin preparations were used to measure CGRP release induced by noxious heat (47 degrees C) and capsaicin (0.5 mu M), stimuli known to activate the capsaicin receptor TRPV1. At low concentration (0.1 mu M) both cannabinoids inhibited stimulated CGRP release by 34-65%, which effects were absent under CBI block by AM 251 and in global CB1 but not TRPV1 knockout mice. At high concentration (100 mu M) both cannabinoids evoked CGRP release by themselves and desensitized subsequent heat responses, which effects were absent under TRPV1 block by BCTC and in global TRPV1 but not CBI knockouts. A lower (0.01 mu M) and the intermediate concentrations (1 and 10 mu M) of cannabinoids were ineffective. Excitatory and desensitizing effects were not more expressed (disinhibited) in CB1(-/-), inhibitory effects not stronger in TRPV1(-/-). CGRP release induced by unspecific depolarization (KCl) was not modulated by cannabinoids. An incidental finding was that global CB1(-/-) showed reduced heat sensitivity, almost as low as TRPV1(-/-) and in accord with their behavioral phenotype. In conclusion, the antinociceptive potency of peripherally acting CB1 agonists is not restrained by opposing irritant effects through TRPV1 but by their own limited efficacy and narrow concentration-response relationship. (C) 2011 Elsevier Ltd. All rights reserved.