Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice.
Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice.
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DOI：
10.1371/journal.pone.0074706
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gaveriaux-Ruff C
中科院分区：
文献类型：
--
作者：
Weibel R;Reiss D;Karchewski L;Gardon O;Matifas A;Filliol D;Becker JA;Wood JN;Kieffer BL;Gaveriaux-Ruff C
阿片类药物是治疗剧烈疼痛的强效药物，通过分布在神经系统各处的u阿片受体发挥作用。它们的临床应用受到中枢调节的不良反应的阻碍，包括恶心或呼吸抑制。在这里，我们使用遗传学方法来研究外周MU阿片受体作为疼痛治疗靶点的潜力。我们产生了条件性基因敲除(CKO)小鼠，其中Mu阿片受体在初级传入Nav1.8阳性神经元中被特异性删除。突变的动物在急性伤害性感觉、炎性疼痛、阿片剂诱导的止痛和便秘方面与对照组进行了比较。CKO组小鼠背根神经节内Mu受体阳性神经元减少76%，Mu受体mRNA减少60%。在急性疼痛模型中，突变小鼠表现出对热、机械、内脏和化学刺激的正常反应，以及不变的吗啡抗伤害感受和对抗伤害感受的耐受性。在完全弗氏佐剂后，CKO和对照组小鼠也出现了类似的炎性疼痛。然而，在炎症模型中，阿片剂诱导的(吗啡、芬太尼和洛哌丁胺)镇痛作用在突变小鼠中与对照组相比减少，并在低剂量时消失。在CKO小鼠中，吗啡诱导的便秘保持完好。因此，我们首次从基因上证明了u阿片受体在Nav1.8阳性感觉神经元水平上部分介导阿片类镇痛作用。在我们的研究中，这种机制在炎性疼痛的条件下工作，而不是在伤害性条件下工作。以前的药理学表明，外周阿片类药物可能在临床上有用，我们的数据进一步证明，Nav1.8神经元相关的u阿片受体是缓解某些形式的持续性疼痛的可行靶点。
Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.
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影响因子：
5.3
作者：
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通讯作者：
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25
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Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
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De Koninck Y
影响因子：
2.5
作者：
Gautron, Laurent;Sakata, Ichiro;Udit, Swalpa;Zigman, Jeffrey M.;Wood, John N.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
影响因子：
3.6
作者：
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通讯作者：
Zoellner, Christian