Opioid Use Disorder (OUD) and opioid‐related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identified Hnrnph1 as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work shows that hnRNP H1, the RNA‐binding protein encoded by Hnrnph1, post‐transcriptionally regulates Oprm1 (mu opioid receptor gene)—the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis that Hnrnph1 mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl. Hnrnph1 mutants showed reduced sensitivity to fentanyl‐induced locomotor activity, along with a female‐specific reduction in, and a male‐specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.). Hnrnph1 mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference (CPP). Male Hnrnph1 mutants showed reduced fentanyl reinforcement. Hnrnph1 mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl‐induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest that Hnrnph1 dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.

中文翻译：

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Hnrnph1 突变对芬太尼成瘾相关行为的性别依赖性影响，但对小鼠的镇痛作用无影响

阿片类药物使用障碍 (OUD) 和阿片类药物相关死亡仍然是美国的主要公共卫生问题。环境和遗传因素都会影响 OUD 的风险。我们之前将Hnrnph1确定为甲基苯丙胺的兴奋剂、奖励和增强特性的数量性状基因。先前的工作表明，hnRNP H1（由Hnrnph1编码的 RNA 结合蛋白）在转录后调节Oprm1（mu 阿片受体基因）——阿片类药物治疗和成瘾特性的主要分子靶点。因为遗传变异可以对多种滥用药物引起的行为产生多效性影响，在目前的研究中，我们检验了Hnrnph1的假设突变体对μ阿片受体激动剂芬太尼的行为敏感性降低。Hnrnph1突变体显示出对芬太尼诱导的运动活动的敏感性降低，以及在每天注射 3 次 (0.2 mg/kg, ip) 后女性特异性降低和男性特异性诱导运动致敏。Hnrnph1突变体还需要更高剂量的芬太尼才能表现出通过条件性位置偏好 (CPP) 测量的阿片类药物奖励。雄性Hnrnph1突变体表现出减少的芬太尼强化。Hnrnph1突变体也表现出降低的蔗糖动机，表明奖励不足。在基线热伤害感受、芬太尼诱导的镇痛感受、阿片类药物依赖的身体或负面情感体征或感觉运动门控方面未观察到基因型差异。在我们先前工作的背景下，这些发现表明Hnrnph1功能障碍在降低对滥用药物（阿片类药物和精神兴奋剂）的成瘾倾向方面发挥选择性作用，这可以提供新的生物学途径来改善其治疗概况。