Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception
Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception
复制标题
DOI：
10.1038/sj.emboj.7600515
复制
发表时间：
2005-01-26
期刊：
影响因子：
11.4
通讯作者：
Nargeot, J
中科院分区：
文献类型：
--
作者：
Bourinet, E;Alloui, A;Nargeot, J
止痛疗法仍然有限，有时效果不佳，因此迫切需要为创新药物的开发寻找新的靶点。为了验证阻断T型钙通道以减少伤害性感觉的潜在效用，我们探索了鞘内注射针对新近发现的T型钙通道家族(Ca(V)3.1、Ca(V)3.2和Ca(V)3.3)的寡核苷酸反义寡核苷酸对健康和单神经病大鼠对伤害性刺激反应的影响。我们的结果表明，针对Ca(V)3.2的反义基因可以抑制伤害性背根神经节神经元中Ca(V)3.2基因和蛋白的表达，并显著降低其‘Ca(V)3.2-like’T-型电流。同时，反义治疗产生了主要的抗伤害性、抗痛觉过敏和抗痛觉过敏性作用，提示Ca(V)3.2在急、慢性疼痛状态中起主要的致痛作用。综上所述，这些结果提供了将Ca(V)3.2 T型通道与痛觉联系起来的直接证据，并提示Ca(V)3.2可能为疼痛的治疗提供了一个特定的分子靶点。
Analgesic therapies are still limited and sometimes poorly effective, therefore finding new targets for the development of innovative drugs is urgently needed. In order to validate the potential utility of blocking T-type calcium channels to reduce nociception, we explored the effects of intrathecally administered oligodeoxynucleotide antisenses, specific to the recently identified T-type calcium channel family (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3), on reactions to noxious stimuli in healthy and mononeuropathic rats. Our results demonstrate that the antisense targeting Ca(V)3.2 induced a knockdown of the Ca(V)3.2 mRNA and protein expression as well as a large reduction of 'Ca(V)3.2-like' T-type currents in nociceptive dorsal root ganglion neurons. Concomitantly, the antisense treatment resulted in major antinociceptive, anti-hyperalgesic, and anti-allodynic effects, suggesting that Ca(V)3.2 plays a major pronociceptive role in acute and chronic pain states. Taken together, the results provide direct evidence linking Ca(V)3.2 T-type channels to pain perception and suggest that Ca(V)3.2 may offer a specific molecular target for the treatment of pain.