Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Sci Adv. 2022 Apr 29;8(17):eabj5586. doi: 10.1126/sciadv.abj5586. Epub 2022 Apr 27.
The comorbidity of chronic pain and mental dysfunctions such as depression and anxiety disorders has long been recognized, but the underlying mechanisms remain poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated neuronal plasticity in the bed nucleus of the stria terminalis (BNST), which plays a critical role in chronic pain-induced maladaptive anxiety. Electrophysiology demonstrated that chronic pain increased inhibitory inputs to lateral hypothalamus (LH)-projecting BNST neurons. Chemogenetic manipulation revealed that sustained suppression of LH-projecting BNST neurons played a crucial role in chronic pain-induced anxiety. Furthermore, using a molecular genetic approach, we demonstrated that chronic pain elevated the excitability of a specific subpopulation of BNST neurons, which express cocaine- and amphetamine-regulated transcript (CART). The elevated excitability of CART-positive neurons caused the increased inhibitory inputs to LH-projecting BNST neurons, thereby inducing anxiety-like behavior. These findings shed light on how chronic pain induces psychiatric disorders, characterized by maladaptive anxiety.
慢性疼痛与精神功能障碍（如抑郁症和焦虑症）的共病早已为人所知，但潜在的机制仍知之甚少。在这里，我们使用神经病理性疼痛的小鼠模型，证明了终纹床核（BNST）中的神经元可塑性，BNST 在慢性疼痛引起的适应不良性焦虑中起着关键作用。电生理学表明，慢性疼痛增加了外侧下丘脑（LH）投射 BNST 神经元的抑制性输入。化学遗传操作表明，持续抑制 LH 投射 BNST 神经元在慢性疼痛引起的焦虑中起着至关重要的作用。此外，我们使用分子遗传学方法证明，慢性疼痛会增加 BNST 神经元中特定亚群的兴奋性，这些神经元表达可卡因和安非他命调节转录物（CART）。CART 阳性神经元的兴奋性增加导致 LH 投射 BNST 神经元的抑制性输入增加，从而引起焦虑样行为。这些发现揭示了慢性疼痛如何引起以适应不良性焦虑为特征的精神疾病。
