Floris Gabriele, Zanda Mary Tresa, Dabrowski Konrad R, Daws Stephanie E
Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA.
Department of Neural Sciences, Temple University, Philadelphia, PA, USA.
Transl Psychiatry. 2024 Dec 19;14(1):500. doi: 10.1038/s41398-024-03203-4.
Recent progress in psychiatric research has highlighted neuroinflammation in the pathophysiology of opioid use disorder (OUD), suggesting that heightened immune responses in the brain may exacerbate opioid-related mechanisms. However, the molecular mechanisms resulting from neuroinflammation that impact opioid-induced behaviors and transcriptional pathways remain poorly understood. In this study, we have begun to address this critical knowledge gap by exploring the intersection between neuroinflammation and exposure to the opioid heroin, utilizing lipopolysaccharide (LPS)-induced neuroinflammation, to investigate transcriptional changes in the nucleus accumbens (NAc), an essential region in the mesolimbic dopamine system that mediates opioid reward. By integrating RNA sequencing with bioinformatic and statistical analyses, we observed significant transcriptional overlaps between neuroinflammation and experimenter-administered heroin exposure in the NAc. Furthermore, we identified a subset of NAc genes synergistically regulated by LPS and heroin, suggesting that LPS history may exacerbate some heroin-induced molecular neuroadaptations. We extended our findings to examine the impact of neuroinflammatory history on responsiveness to heroin in a locomotor sensitization assay and observed LPS-induced exacerbation of heroin sensitization, indicating that neuroinflammation may increase sensitivity to opioids' behavioral effects. Lastly, we performed comparative analysis of the NAc transcriptional profiles of LPS-heroin rats with those obtained from voluntary heroin intake in a rat model of heroin self-administration (SA) and published human OUD datasets. We observed significant convergence of the three datasets and identified transcriptional patterns in the preclinical models that recapitulated human OUD neuropathology, highlighting the utility of preclinical models to further investigate molecular mechanisms of OUD pathology. Overall, our study elucidates transcriptional interconnections between neuroinflammation and heroin exposure, and also provides evidence of the behavioral ramifications of such interactions. By bridging the gap between neuroinflammation and heroin exposure at the transcriptional level, our work provides valuable insights for future research aimed at mitigating the influence of inflammatory pathways in OUD.
精神病学研究的最新进展突出了神经炎症在阿片类药物使用障碍（OUD）病理生理学中的作用，这表明大脑中增强的免疫反应可能会加剧与阿片类药物相关的机制。然而，神经炎症导致的影响阿片类药物诱导行为和转录途径的分子机制仍知之甚少。在本研究中，我们通过探索神经炎症与阿片类药物海洛因暴露之间的交叉点，利用脂多糖（LPS）诱导的神经炎症，来研究伏隔核（NAc）中的转录变化，伏隔核是中脑边缘多巴胺系统中介导阿片类药物奖赏的关键区域，从而开始填补这一关键的知识空白。通过将RNA测序与生物信息学和统计分析相结合，我们观察到神经炎症与实验者给予海洛因暴露在伏隔核中存在显著的转录重叠。此外，我们鉴定出一组受LPS和海洛因协同调节的伏隔核基因，这表明LPS暴露史可能会加剧一些海洛因诱导的分子神经适应性变化。我们扩展了研究结果，在运动敏化试验中研究神经炎症史对海洛因反应性的影响，并观察到LPS诱导的海洛因敏化加剧，这表明神经炎症可能会增加对阿片类药物行为效应的敏感性。最后，我们对LPS-海洛因处理大鼠的伏隔核转录谱与在海洛因自我给药（SA）大鼠模型中自愿摄入海洛因以及已发表的人类OUD数据集中获得的转录谱进行了比较分析。我们观察到这三个数据集有显著的趋同，并在临床前模型中鉴定出概括人类OUD神经病理学的转录模式，突出了临床前模型在进一步研究OUD病理学分子机制方面的实用性。总体而言，我们的研究阐明了神经炎症与海洛因暴露之间的转录联系，并提供了这种相互作用行为后果的证据。通过在转录水平上弥合神经炎症与海洛因暴露之间的差距，我们的工作为未来旨在减轻炎症途径在OUD中影响的研究提供了有价值的见解。
