Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation
Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation
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DOI：
10.1523/jneurosci.1565-06.2008
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发表时间：
2008-01-30
影响因子：
5.3
通讯作者：
Hargreaves, Kenneth M.
中科院分区：
文献类型：
--
作者：
Akopian, Armen N.;Ruparel, Nikita B.;Hargreaves, Kenneth M.
虽然大麻素激动剂R-（+）-（2，3-二氢-5-甲基-3-[（4-吗啉基）甲基]吡咯[1，2，3-de]-1，4-苯并恶嗪-6-基）-（1-萘基）甲酮甲磺酸盐[WIN 55，212 -2（WIN）]和（R，S）-3-（2-碘-5-硝基苯甲酰基）-1-（1-甲基-2-哌啶基甲基）-1H-吲哚（AM 1241）在炎性疼痛模型中发挥外周抗痛觉过敏作用，大麻素诱导的伤害感受感觉神经元抑制的机制尚未完全研究。由于TRPV 1和TRPA 1通道在控制炎性疼痛模型中的痛觉过敏中起重要作用，我们研究了WIN和AM 1241对它们的调节。WIN（>5 μ M）和AM 1241（> 30 μ M）的应用抑制感觉神经元对辣椒素和芥子油的反应。为了确定抑制的潜在机制，我们评估了大麻素对伤害感受器的影响。WIN和AM 1241通过非选择性Ca 2+渗透通道以浓度依赖性方式兴奋感觉神经元。TRP通道在CHO细胞中的表达表明，WIN和AM 1241都激活TRPA 1，并通过这样做，减弱辣椒素和芥子油反应。使用TRPA 1特异性小干扰RNA或TRPA 1缺陷小鼠，我们表明TRPA 1通道是WIN和芥子油激活感觉神经元的唯一靶点。相反，AM 1241对感觉神经元的激活是由TRPA 1和一个未知的通道介导的。神经元中TRPA 1活性的敲低完全消除了WIN和AM 1241对辣椒素激活电流的脱敏作用。此外，在TRPA 1缺失突变小鼠中，通过外周作用对辣椒素诱发的伤害反应行为的WIN-AM 1241诱导的抑制被逆转。总之，这项研究表明，某些大麻素通过激活感觉神经元上的TRPA 1通道发挥其外周抗伤害作用。
Although the cannabinoid agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl) methyl] pyrol[ 1,2,3-de]-1,4-benzoxazin-6-yl)-(1-naphthalenyl) methanone mesylate [WIN 55,212-2 (WIN)] and (R, S)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) exert peripheral antihyperalgesia in inflammatory pain models, the mechanism for cannabinoid-induced inhibition of nociceptive sensory neurons has not been fully studied. Because TRPV1 and TRPA1 channels play important roles in controlling hyperalgesia in inflammatory pain models, we investigated their modulation by WIN and AM1241. The applications of WIN (>5 mu M) and AM1241 (> 30 mu M) inhibit responses of sensory neurons to capsaicin and mustard oil. To determine potential mechanisms for the inhibition, we evaluated cannabinoid effects on nociceptors. WIN and AM1241 excite sensory neurons in a concentration-dependent manner via a nonselective Ca2+-permeable channel. The expression of TRP channels in CHO cells demonstrates that both WIN and AM1241 activate TRPA1 and, by doing so, attenuate capsaicin and mustard oil responses. Using TRPA1-specific small interfering RNA or TRPA1-deficient mice, we show that the TRPA1 channel is a sole target through which WIN and mustard oil activate sensory neurons. In contrast, AM1241 activation of sensory neurons is mediated by TRPA1 and an unknown channel. The knockdown of TRPA1 activity in neurons completely eliminates the desensitizing effects of WIN and AM1241 on capsaicin-activated currents. Furthermore, the WIN-or AM1241-induced inhibition of capsaicin-evoked nocifensive behavior via peripheral actions is reversed in TRPA1 null-mutant mice. Together, this study demonstrates that certain cannabinoids exert their peripheral antinocifensive actions via activation of the TRPA1 channel on sensory neurons.