Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, and.
J Neurosci. 2020 Mar 11;40(11):2332-2342. doi: 10.1523/JNEUROSCI.1259-19.2020. Epub 2020 Jan 31.
Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase Sirtuin 1 (SIRT1) in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein levels in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the α promoter. These results suggest that, by transcriptional repression of α in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders. Chronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1-CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to the development of chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain.
情绪障碍是常见的共病状况，会进一步加重慢性疼痛的严重程度和慢性化。然而，在相似的疼痛条件下，个体对慢性疼痛的发展表现出相当大的易感性。在这项针对慢性神经病理性疼痛雄性大鼠和小鼠模型的研究中，我们确定了中央杏仁核中的组蛋白去乙酰化酶 Sirtuin 1（SIRT1）是一种关键的表观遗传调节剂，它控制着个体对慢性疼痛易感性的共病情绪障碍的发展。我们发现，在疼痛条件下容易出现焦虑和抑郁行为的动物，中央杏仁核中的 SIRT1 蛋白水平降低，但对情绪障碍具有抵抗力的动物则没有。局部 SIRT1 的病毒过表达逆转了这种易感性，但局部 SIRT1 的病毒敲低则模拟了疼痛效应，在无痛动物中引起了疼痛易感性。SIRT1 的作用与 CaMKIIα 下调和组蛋白 H3 赖氨酸 9 在 α 启动子上的去乙酰化有关。这些结果表明，SIRT1 通过中央杏仁核中 α 的转录抑制作用，在慢性疼痛条件下发挥作用，防止情绪疼痛易感性。这项研究表明，SIRT1 可能作为一种潜在的治疗分子，用于治疗具有易感性情绪障碍的慢性疼痛。慢性疼痛是一种普遍存在的神经系统疾病，目前尚无有效治疗方法。疼痛患者对慢性疼痛的发展表现出相当大的易感性，表明疼痛易感性存在个体基础的分子机制，但在当前的临床前研究中几乎没有涉及。在这项研究中，我们已经确定组蛋白去乙酰化酶 Sirtuin 1（SIRT1）是一种关键调节因子，控制着这种疼痛易感性。这项研究揭示了中央杏仁核中的 SIRT1-CaMKIIaα 通路作为一种表观遗传机制，防止慢性疼痛下共病情绪障碍的发展，其功能障碍导致慢性疼痛发展的易感性增加。这些发现表明，SIRT1 激活剂可能用于治疗慢性疼痛的新型个体化治疗方法。
