Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis
Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis
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DOI：
10.1073/pnas.93.9.3995
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发表时间：
1996-04-30
影响因子：
11.1
通讯作者：
Low, MJ
中科院分区：
文献类型：
--
作者：
Rubinstein, M;Mogil, JS;Low, MJ
β-内啡肽在内源性疼痛抑制中的生理作用是通过在小鼠胚胎干细胞中对阿黑皮素原基因进行靶向诱变来研究的。阿黑皮素原基因第179位的酪氨酸密码子被转化为提前翻译的终止密码子。由此产生的转基因小鼠没有表现出明显的发育或行为改变，并具有正常功能的下丘脑-垂体-肾上腺轴。选择性缺乏β-内啡肽的纯合子转基因小鼠对吗啡的镇痛反应正常，表明存在功能性μ-阿片受体。然而，这些小鼠缺乏轻度游泳应激诱导的阿片类（纳洛酮可逆）镇痛。突变小鼠也显示显着更大的非阿片类镇痛反应冷水游泳应激与对照组相比，并显示矛盾的纳洛酮诱导的镇痛。这些变化可能反映了替代性疼痛抑制机制的代偿性上调。
A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.