The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent association of VitD levels with self-reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin-seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.

当前的阿片类药物流行需要更好地了解导致阿片类药物成瘾的遗传和环境因素。在这里，我们报告了被诊断为阿片类药物使用障碍的患者中维生素 D (VitD) 缺乏症的患病率增加，并且 VitD 水平与自我报告的阿片类药物使用呈反向和剂量依赖性关联。我们使用了多种药理学方法和遗传小鼠模型，发现 VitD 信号传导的缺陷会放大外源性阿片类药物反应，这些反应在 VitD 信号传导恢复后会正常化。同样，由紫外线 (UV) 辐射触发的生理性内源性阿片类镇痛和奖赏反应被 VitD 信号抑制，表明存在一个反馈回路，即 VitD 缺乏会产生增加的紫外线/内啡肽寻求行为，直到通过皮肤 VitD 合成恢复 VitD 水平。这种反馈可能具有最大化 VitD 合成的进化优势。然而，与紫外线照射不同，外源性阿片类药物的使用不会伴随 VitD 合成（及其阿片类药物抑制作用），这会导致适应不良的成瘾行为。