Department of Anesthesiology, Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan.
J Anesth. 2011 Aug;25(4):549-57. doi: 10.1007/s00540-011-1168-6. Epub 2011 May 24.
Besides being administered systemically for sedation and analgesia, α(2)-agonists such as dexmedetomidine and clonidine have been administered with intrathecal, epidural, or perineural injections, leading to an antinociceptive effect at the spinal cord or peripheral nerve level. However, the mechanism for this remains unclear. In the present study, we examined whether dexmedetomidine and clonidine could inhibit the function of tetrodotoxin-sensitive Na(+) channels, which play important roles in the generation of pain.
Cultured bovine adrenal chromaffin cells expressing the tetrodotoxin-sensitive Na(v)1.7 Na(+) channel isoform were incubated in KRP buffer containing 2 μCi (22)NaCl for 5 min without or with dexmedetomidine or clonidine in the absence or presence of veratridine, α-scorpion venom, β-scorpion venom, Ptychodiscus brevis toxin-3 or ouabain. Cells were then washed and counted radioactively.
Dexmedetomidine and clonidine reduced veratridine-induced (22)Na(+) influx via Na(v)1.7 in a concentration-dependent manner (EC(50) = 50 μM and 530 μM), even in the presence of ouabain, an inhibitor of Na(+), K(+)-ATPase. Dexmedetomidine and clonidine shifted the concentration-response curve of veratridine for (22)Na(+) influx downward without altering the EC(50) of veratridine. Atipamezole and yohimbine, α(2)-antagonists, did not prevent the inhibition of veratridine-induced (22)Na(+) influx by dexmedetomidine. Dexmedetomidine and clonidine combined with lidocaine induced more inhibition of veratridine-induced (22)Na(+) influx than each drug did individually. Atipamezole and yohimbine did not prevent the lidocaine-enhancing effect of dexmedetomidine and clonidine.
Dexmedetomidine and clonidine inhibit the function of Na(v)1.7 independent of α(2)-adrenoceptor. These results may lead to a deeper understanding of the peripheral antinociceptive effects of α (2)-agonists.
除了全身给予镇静和镇痛作用外，α（2）-激动剂如右美托咪定和可乐定也已通过鞘内、硬膜外或神经周围注射给予，从而在脊髓或外周神经水平产生镇痛作用。然而，其机制尚不清楚。在本研究中，我们研究了右美托咪定和可乐定是否可以抑制河豚毒素敏感的 Na(+)通道的功能，该通道在疼痛产生中起着重要作用。
在含有 2 μCi（22）NaCl 的 KRP 缓冲液中孵育表达河豚毒素敏感的 Na(v)1.7 Na(+)通道同工型的培养牛肾上腺嗜铬细胞瘤细胞 5 分钟，而没有或存在右美托咪定或可乐定在没有或存在藜芦碱、α-蝎毒素、β-蝎毒素、Ptychodiscus brevis 毒素-3 或哇巴因的情况下。然后将细胞洗涤并放射性计数。
右美托咪定和可乐定以浓度依赖性方式降低了藜芦碱诱导的（22）Na(+)内流（EC(50)分别为 50 μM 和 530 μM），即使在 Na(+)，K(+)-ATP 酶抑制剂哇巴因存在的情况下也是如此。右美托咪定和可乐定使藜芦碱对（22）Na(+)内流的浓度-反应曲线向下移动，而不改变藜芦碱的 EC(50)。α(2)-拮抗剂阿替美唑和育亨宾并没有阻止右美托咪定抑制藜芦碱诱导的（22）Na(+)内流。右美托咪定和可乐定与利多卡因联合使用比单独使用每种药物诱导的藜芦碱诱导的（22）Na(+)内流抑制更多。阿替美唑和育亨宾并没有阻止右美托咪定和可乐定增强利多卡因的作用。
右美托咪定和可乐定抑制 Na(v)1.7 的功能独立于 α(2)-肾上腺素能受体。这些结果可能导致对 α(2)-激动剂的外周镇痛作用有更深入的了解。
