Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

IF 5.9 1区 医学 Q1 ANESTHESIOLOGY PAIN® Pub Date : 2024-12-01 Epub Date: 2024-07-09 DOI:10.1097/j.pain.0000000000003316
Randal A Serafini, Zahra Farzinpour, Vishwendra Patel, Abigail M Kelley, Molly Estill, Kerri D Pryce, Farhana Sakloth, Collin D Teague, Angelica Torres-Berrio, Eric J Nestler, Li Shen, Schahram Akbarian, Anushree N Karkhanis, Robert D Blitzer, Venetia Zachariou
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Abstract

Abstract: Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.

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核仁肌细胞增强因子2C介导维持周围神经损伤引起的生理和行为适应不良。
摘要:临床前和临床研究表明,在慢性疼痛状态下,神经核(NAc)的可塑性和活性发生了改变,这为慢性疼痛的治疗提供了重要途径。在这项研究中,我们证明了神经元活性和可塑性的主要调节因子--肌细胞增强因子2C(MEF2C)在神经损伤(SNI)后受到抑制。病毒介导的Mef2c在NAc神经元中的过表达部分改善了SNI小鼠的感觉过敏和情绪行为,同时也改变了与突触信号转导相关的转录通路。Mef2c的过表达还逆转了SNI诱导的NAc神经元多巴胺阶段性释放电位和神经元过度兴奋性。Mef2c过表达诱导的转录变化不同于地西泮治疗后观察到的变化,这表明其作用机制不同于抗抑郁药。总之,我们的研究表明,对NAc中MEF2C调控机制的干预足以破坏慢性疼痛状态的维持,为神经病理性疼痛提供了潜在的新治疗途径。
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来源期刊
PAIN®
PAIN® 医学-临床神经学
CiteScore
12.50
自引率
8.10%
发文量
242
审稿时长
9 months
期刊介绍: PAIN® is the official publication of the International Association for the Study of Pain and publishes original research on the nature,mechanisms and treatment of pain.PAIN® provides a forum for the dissemination of research in the basic and clinical sciences of multidisciplinary interest.
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