A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7.
A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7.
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小鼠和人类缺乏钠通道Na（v）1.7的镇痛的中心机制。
DOI：
10.1016/j.neuron.2021.03.012
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发表时间：
2021-05-05
期刊：
影响因子：
16.2
通讯作者：
Wood JN
中科院分区：
文献类型：
--
作者：
MacDonald DI;Sikandar S;Weiss J;Pyrski M;Luiz AP;Millet Q;Emery EC;Mancini F;Iannetti GD;Alles SRA;Arcangeletti M;Zhao J;Cox JJ;Brownstone RM;Zufall F;Wood JN
人类中编码电压门控钠通道 NaV1.7 的 SCN9A 缺失会导致严重的疼痛不敏感和嗅觉丧失。在小鼠感觉神经元中条件性删除 NaV1.7 也能消除疼痛，这表明镇痛的部位是伤害感受器。在这里，我们利用体内钙成像和细胞外记录证明，NaV1.7 敲除小鼠具有基本正常的伤害感受器活性。然而，阿片依赖性机制大大减少了脊髓中伤害感受器中央末端的突触传递。阿片类拮抗剂的中枢而非外周应用也可显着逆转镇痛作用。相比之下，嗅觉感觉神经元释放神经递质的缺乏与阿片类药物无关。具有 NaV1.7 缺失突变的男性和女性表现出纳洛酮可逆镇痛作用。因此，抑制神经递质释放是小鼠和人类 Nav1.7 缺失突变体嗅觉丧失和镇痛的主要机制。钠通道 NaV1.7 的缺失可消除疼痛，但不会沉默外周伤害感受器 背角的突触输入受到阿片类药物依赖性机制的损害 嗅觉感觉神经元的神经传递受损，与阿片类药物无关 阻断阿片类受体可逆转缺乏 NaV1.7 的小鼠和人类的镇痛作用 外周钠通道 NaV1.7 的缺失会导致对疼痛严重不敏感。麦克唐纳等人。显示伤害感受器活性不受 NaV1.7 缺失的影响，但背角的突触输入受到阿片类药物依赖性机制的影响。阻断中枢阿片受体可逆转缺乏 NaV1.7 的小鼠和人类的镇痛作用。
Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of NaV1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that NaV1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with NaV1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants. Loss of sodium channel NaV1.7 abolishes pain without silencing peripheral nociceptors Synaptic input to dorsal horn is compromised by an opioid-dependent mechanism Impaired neurotransmission from olfactory sensory neurons is opioid independent Blocking opioid receptors reverses analgesia in mice and humans lacking NaV1.7 Loss of the peripheral sodium channel NaV1.7 causes profound insensitivity to pain. MacDonald et al. show that nociceptor activity is unaffected by NaV1.7 deletion but that synaptic input to the dorsal horn is compromised by an opioid-dependent mechanism. Blocking central opioid receptors reverses analgesia in mice and humans lacking NaV1.7.
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