Comorbid anxiety and depressive symptoms in chronic pain are a common health problem, but the underlying mechanisms remain unclear. Previously, we have demonstrated that sensitization of the CeA neurons via decreased GABAergic inhibition contributes to anxiety-like behaviors in neuropathic pain rats. In this study, by using male Sprague Dawley rats, we reported that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain. Bilateral electrolytic lesions of CeA, but not lateral/basolateral nucleus of the amygdala (LA/BLA), abrogated both pain hypersensitivity and aversive and depressive symptoms of neuropathic rats induced by spinal nerve ligation (SNL). Moreover, SNL rats showed structural and functional neuroplasticity manifested as reduced dendritic spines on the CeA neurons and enhanced LTD at the LA/BLA-CeA synapse. Disruption of GluA2-containing AMPAR trafficking and endocytosis from synapses using synthetic peptides, either pep2-EVKI or Tat-GluA2_(3Y), restored the enhanced LTD at the LA/BLA-CeA synapse, and alleviated the mechanical allodynia and comorbid aversive and depressive symptoms in neuropathic rats, indicating that the endocytosis of GluA2-containing AMPARs from synapses is probably involved in the LTD at the LA/BLA-CeA synapse and the comorbid aversive and depressive symptoms in neuropathic pain in SNL-operated rats. These data provide a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlight that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.

SIGNIFICANCE STATEMENT Several studies have demonstrated the high comorbidity of negative affective disorders in patients with chronic pain. Understanding the affective aspects related to chronic pain may facilitate the development of novel therapies for more effective management. Here, we unravel that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain, and LTD at the amygdaloid LA/BLA-CeA synapse mediated by GluA2-containing AMPAR endocytosis underlies the comorbid aversive and depressive symptoms in neuropathic pain. This study provides a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlights that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.

慢性疼痛中的共病焦虑和抑郁症状是一个常见的健康问题，但其潜在机制尚不清楚。以前，我们已经证明通过降低 GABA 能抑制对 CeA 神经元的敏化有助于神经性疼痛大鼠的焦虑样行为。在这项研究中，通过使用雄性 Sprague Dawley 大鼠，我们报告了 CeA 在处理神经性疼痛的感觉和负面情绪影响成分方面起着关键作用。CeA 的双侧电解损伤，但不是杏仁核的外侧/基底外侧核 (LA/BLA)，消除了由脊神经结扎术 (SNL) 引起的神经性大鼠的疼痛超敏反应和厌恶和抑郁症状。而且，SNL 大鼠表现出结构和功能的神经可塑性，表现为 CeA 神经元上的树突棘减少，LA/BLA-CeA 突触的 LTD 增强。使用合成肽破坏含有 GluA2 的 AMPAR 运输和突触内吞作用，pep2-evki 或 Tat-GluA2_(3Y)，恢复了 LA/BLA-CeA 突触增强的 LTD，并减轻了神经性大鼠的机械性异常性疼痛和共存的厌恶和抑郁症状，表明突触中含有 GluA2 的 AMPAR 的内吞作用可能参与了 LTD LA/BLA-CeA 突触和 SNL 手术大鼠神经性疼痛中的共病厌恶和抑郁症状。这些数据为阐明神经性疼痛中的共病厌恶和抑郁症状提供了一种新机制，并强调杏仁核中的结构和功能神经可塑性可能是重要的，作为慢性疼痛共病负面情绪情感障碍的有希望的治疗靶点。

意义声明几项研究表明，慢性疼痛患者的负面情感障碍具有很高的合并症。了解与慢性疼痛相关的情感方面可能有助于开发新疗法以实现更有效的管理。在这里，我们揭示了 CeA 在处理神经性疼痛的感觉和负面情绪影响成分中起着关键作用，并且由含 GluA2 的 AMPAR 内吞作用介导的杏仁核 LA/BLA-CeA 突触中的 LTD 是共病厌恶和抑郁症状的基础在神经性疼痛中。