Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.
Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.
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DOI：
10.1016/j.brainresbull.2015.10.007
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发表时间：
2016-05
影响因子：
3.8
通讯作者：
Morgan DJ
中科院分区：
文献类型：
--
作者：
Henderson-Redmond AN;Yuill MB;Lowe TE;Kline AM;Zee ML;Guindon J;Morgan DJ
阿片类药物的奖赏和抗伤害作用是通过μ阿片受体介导的。该受体中的A118 G单核苷酸多态性与药物成瘾和疼痛反应的差异有关。临床和临床前研究发现，G等位基因与海洛因奖励和自我给药增加、术后疼痛增加和对阿片类药物的镇痛反应降低相关。对“人源化”118 AA或118 GG等位基因纯合的雄性和雌性小鼠进行评价，以检验118 GG小鼠对吗啡的奖励和抗伤害感受作用较不敏感的假设。我们发现，118 AA和118 GG两种性别的小鼠对吗啡都产生了条件性位置偏爱。所有小鼠均对吗啡的急性镇痛和降温作用产生耐受性。然而，吗啡耐受性AA和GG小鼠之间没有差异。我们还研究了累积吗啡剂量的急性镇痛和降温效应的敏感性。我们发现118 GG小鼠在热板上对10 mg/kg吗啡表现出降低的低温和抗伤害性反应。最后，我们研究了基础疼痛反应和吗啡诱导的镇痛在福尔马林试验中的炎性疼痛。在福尔马林试验中，我们没有发现性别或基因型在基础疼痛反应或吗啡诱导的抗伤害感受方面的差异。我们的数据表明，GG等位基因在小鼠中的纯合表达减弱吗啡诱导的低温和热板抗伤害性感受，但不改变吗啡CPP，吗啡耐受，或基础炎性疼痛反应。
The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the “humanized” 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GGmice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the acute antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the acute antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10 mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response.