Program in Neuroscience, Department of Pharmacology and Toxicology, The State University of New York at Buffalo, 955 Main Street, Buffalo, NY, 14203, USA.
Department of Biomedical Sciences, John C. Edwards School of Medicine, Marshall University, 1700, 3rd Avenue, Huntington, WV, 25755, USA.
Psychopharmacology (Berl). 2022 Nov;239(11):3539-3550. doi: 10.1007/s00213-022-06226-1. Epub 2022 Sep 13.
Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.
慢性疼痛可能是一种使人衰弱的疾病，导致生活几乎各个方面都发生深刻变化。然而，人们认为依赖羟考酮等阿片类药物来进行疼痛管理会引发依赖和成瘾性。阿片类药物缓解疼痛并可能转变为成瘾的神经生物学交叉点尚不清楚。通过对完全弗氏佐剂（CFA）诱导的慢性炎症大鼠进行 RNA 测序途径分析，我们发现 CFA 与羟考酮联合使用在中前额叶皮层（mPFC；疼痛和奖励信号整合的大脑区域）中引起的转录特征与 CFA 或羟考酮单独引起的特征不同。然而，所有接受羟考酮的动物的 Egr3 表达均增强。此外，在接受羟考酮的动物中，mPFC 中 EGR3 的病毒介导过表达增加了机械性疼痛缓解，但没有增加疼痛的情感方面，而通过 NFAT 抑制 EGR3 的药理学抑制减轻了机械性疼痛缓解。Egr3 的过表达还增加了在渐进比例测试中获得羟考酮输注的动机，而不改变羟考酮自我给药的获得或维持。总之，这些数据表明，mPFC 中的 EGR3 处于伤害感受和类似成瘾行为的交叉点。
