Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons.
Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons.
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右美托咪定通过大鼠背根神经节神经元中的 Gi/o 依赖性途径抑制河豚毒素耐药 Nav1.8 钠通道活性。
DOI：
10.1186/s13041-015-0105-2
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发表时间：
2015-03-03
期刊：
影响因子：
3.6
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Gu XY;Liu BL;Zang KK;Yang L;Xu H;Pan HL;Zhao ZQ;Zhang YQ
全身给予右美托咪定（DEX），一种选择性α2肾上腺素能受体（α2-AR）激动剂，可产生镇痛和镇静作用。外周限制性α2-AR拮抗剂可阻断全身性DEX对神经病理性疼痛的镇痛作用，而对镇静作用无影响，提示DEX具有外周镇痛作用。河豚毒素抗性（TTX-R）钠通道Nav1.8在伤害性感觉传导中起重要作用。α2-AR和Nav1.8均存在于小的伤害性DRG神经元中。因此，我们研究了DEX对急性分离的小直径DRG神经元Nav1.8电流的影响。全细胞膜片钳记录表明，DEX浓度依赖性地抑制TTX-R Nav1.8电流在小直径腰DRG神经元。DEX还使Nav1.8的稳态失活曲线向超极化方向移动，增加动作电位阈值，减少电刺激和化学刺激诱发的小直径DRG神经元的放电。α2-AR拮抗剂育亨宾或α 2 A-AR拮抗剂BRL 44408可阻断DEX对Nav1.8电流的抑制作用，但α 2 B-AR拮抗剂imiloxan不能阻断DEX对Nav1.8电流的抑制作用。免疫组化结果显示，Nav1.8主要表达于外周蛋白阳性的小直径DRG神经元，部分神经元为α2A-AR阳性。我们的电生理记录还表明，细胞内应用G蛋白抑制剂GDPβ-s或Gi/o蛋白抑制剂百日咳毒素（PTX），以及浴中应用腺苷酸环化酶（AC）激活剂forskolin或膜渗透性cAMP类似物8-Br-cAMP（8-Br-cAMP），可阻止DEX诱导的Nav1.8电流抑制。PKA抑制剂Rp-cAMP可模拟DEX对Nav1.8电流的抑制作用。我们在初级感觉神经元中通过Gi/o/AC/cAMP/PKA通路建立了α2-AR和Nav1.8之间的功能联系，该通路可能介导DEX的外周镇痛。
Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Nav1.8 currents in acutely dissociated small-diameter DRG neurons. Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Nav1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2A-AR antagonist BRL44408 but not α2B-AR antagonist imiloxan blocked the inhibition of Nav1.8 currents by DEX. Immunohistochemistry results showed that Nav1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Nav1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or Gi/o proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Nav1.8 currents. We established a functional link between α2-AR and Nav1.8 in primary sensory neurons utilizing the Gi/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
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影响因子：
4.8
作者：
Bavencoffe, Alexis;Gkika, Dimitra;Prevarskaya, Natalia
通讯作者：
Prevarskaya, Natalia
影响因子：
1.7
作者：
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影响因子：
7.4
作者：
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作者：
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影响因子：
5.3
作者：
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Sarret, Philippe