Shelton Micah A, Horan Nicole, Xue Xiangning, Maturin Lisa, Eacret Darrell, Michaud Julie, Singh Navsharan, Williams Benjamin R, Gamble Mackenzie C, Seggio Joseph A, Fish Madeline K, Phan BaDoi N, Tseng George C, Blendy Julie A, Solberg Woods Leah C, Palmer Abraham A, George Olivier, Logan Ryan W, Seney Marianne L
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Center for Neuroscience at University of Pittsburgh, Pittsburgh, Pennsylvania.
Biol Psychiatry Glob Open Sci. 2025 Feb 26;5(3):100476. doi: 10.1016/j.bpsgos.2025.100476. eCollection 2025 May.
Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current treatments for OUD are unsuccessful in leading to lasting abstinence in most users. This underscores the lasting effects of chronic opioid use and emphasizes the need to understand the molecular mechanisms of drug seeking and taking and how those alterations persist through acute and protracted withdrawal.
Here, we used RNA sequencing in postmortem human tissue from males ( = 10) and females ( = 10) with OUD and age- and sex-matched control subjects. We compared molecular alterations associated with human OUD in the nucleus accumbens (NAc) to mouse and rat models of nonvolitional ( = 4-5 per group per sex) and volitional ( = 5-6 per group per sex) exposure to opioids across distinct stages of opioid use and withdrawal (acute and prolonged).
We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female rodents in a nonvolitional paradigm at all stages of exposure. Conversely, males with OUD showed an expression profile similar to that of rodents with volitional exposure but only during the acute withdrawal phase. Shared coexpression networks were involved in posttranscriptional modification of RNA and epigenetic modification of chromatin state.
Our results provide fundamental insight into the conserved molecular pathways altered by opioids across species, with evidence suggesting that alterations in females with OUD may be driven by drug exposure, while alterations in males with OUD may be driven by volitional intake.
阿片类物质使用障碍（OUD）已成为一场严重且持续的公共卫生紧急事件。目前针对OUD的治疗方法在使大多数使用者实现持久戒断方面并不成功。这凸显了慢性阿片类物质使用的持久影响，并强调有必要了解觅药和用药的分子机制，以及这些改变如何在急性和迁延性戒断过程中持续存在。
在此，我们对患有OUD的男性（n = 10）和女性（n = 10）以及年龄和性别匹配的对照受试者的死后人体组织进行了RNA测序。我们将伏隔核（NAc）中与人类OUD相关的分子改变，与在阿片类物质使用和戒断的不同阶段（急性和迁延性）非自愿（每组每种性别n = 4 - 5）和自愿（每组每种性别n = 5 - 6）接触阿片类物质的小鼠和大鼠模型进行了比较。
我们发现，患有OUD的女性NAc中的分子特征在暴露的所有阶段都反映了非自愿范式下雌性啮齿动物NAc中的效应。相反，患有OUD的男性仅在急性戒断阶段表现出与自愿接触阿片类物质的啮齿动物相似的表达谱。共享的共表达网络参与了RNA的转录后修饰和染色质状态的表观遗传修饰。
我们的结果为跨物种阿片类物质改变的保守分子途径提供了基本见解，有证据表明，患有OUD的女性的改变可能由药物暴露驱动，而患有OUD的男性的改变可能由自愿摄入驱动。
