Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.
Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.
复制标题
DOI：
10.1126/scisignal.aah4874
复制
发表时间：
2017-01-10
影响因子：
7.3
通讯作者：
Hucho T
中科院分区：
文献类型：
--
作者：
Isensee J;Krahé L;Moeller K;Pereira V;Sexton JE;Sun X;Emery E;Wood JN;Hucho T
电压门控钠通道Nav1.7 （Nav1.7-/-）的遗传缺失导致小鼠和人类终生对疼痛不敏感。一个潜在的原因是感觉神经元中内源性阿片样物质的产生增加。我们分析了Nav1.7缺乏是否改变了感觉神经元中伤害性异三聚体鸟嘌呤核苷酸结合蛋白偶联受体（GPCR）信号传导，例如由GPCR对血清素（原痛觉性）或阿片类物质（抗痛觉性）作出反应的GPCR启动。我们发现，Nav1.7敲除（Nav1.7-/-）小鼠的伤害性神经元，而Nav1.8敲除（Nav1.8-/-）小鼠的伤害性神经元，通过5-HT4受体（g αs偶联的gpcr，刺激环磷酸腺苷的产生，导致蛋白激酶A （PKA）的活性，以及PKA的RIIβ调节亚基的丰度降低）表现出伤害性前血清素能信号传导的减少。同时，g αi偶联mu阿片受体介导的抗伤害性阿片信号传导的作用增强。因此，阿片类药物更有效地抑制河豚毒素抗性钠电流，这对痛觉神经元中引起疼痛的神经元活动很重要。因此，Nav1.7控制着GPCR介导的促痛性和抗痛性细胞内信号传导的功效和平衡，如果没有Nav1.7，这种平衡就会向抗痛性转移，从而导致终身内源性镇痛。
Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide–binding protein–coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1.7 knockout (Nav1.7-/-) mice, but not of Nav1.8 knockout (Nav1.8-/-) mice, exhibited decreased pro-nociceptive serotonergic signaling through the 5-HT4 receptors, which are Gαs-coupled GPCRs that stimulate the production of cyclic adenosine monophosphate resulting in protein kinase A (PKA) activity, as well as reduced abundance of the RIIβ regulatory subunit of PKA. Simultaneously, the efficacy of anti-nociceptive opioid signaling mediated by the Gαi-coupled mu opioid receptor was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Nav1.7 controls the efficacy and balance of GPCR mediated pro- and antinociceptive intracellular signaling, such that without Nav1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.
登录
查看更多内容
影响因子：
4
作者：
Gaskin, Darrell J.;Richard, Patrick
通讯作者：
Richard, Patrick
影响因子：
3.3
作者：
Chattopadhyay M;Zhou Z;Hao S;Mata M;Fink DJ
通讯作者：
Fink DJ
影响因子：
5.8
作者：
Emery EC;Luiz AP;Wood JN
通讯作者：
Wood JN
影响因子：
4.7
作者：
Johnston, CA;Beazely, MA;Watts, VJ
通讯作者：
Watts, VJ
DOI：
10.1073/pnas.1415013111
发表时间：
2014-12-23
影响因子：
11.1
作者：
Livingston, Kathryn E.;Traynor, John R.
通讯作者：
Traynor, John R.