Gao Yuan, Zhang Xue, Liu Xiao-Juan, Sun Yi-Ling, Yin Cui, Tang Dong-Liang, Xiao Cheng, Zhou Chunyi
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, 209 Tonghshan Road, Xuzhou, Jiangsu, 221004, China.
Adv Sci (Weinh). 2025 Jul;12(26):e2503739. doi: 10.1002/advs.202503739. Epub 2025 Apr 7.
The locus coeruleus (LC) noradrenergic (NA) neurons regulate pain and depression through their projections to various downstream nuclei. Although GABAergic (GABA) neurons in and near the LC (LC-GABA neurons) provide inhibitory synaptic inputs to LC-NA neurons, it remains unknown whether they are implicated in neuropathic pain and comorbid depression through LC-NA neurons. This study demonstrates that LC-GABA neurons respond to noxious stimuli with enhanced activity, and stimulation of these neurons elevates pain thresholds and exerts an anti-depressant-like effect in naive and neuropathic pain mice. Conversely, inhibition of LC-GABA neurons leads to hyperalgesia and depression-like behaviors in naive mice and exacerbates existing pain- and depression-like behaviors in neuropathic pain mice. Although LC-GABA neurons inhibit pain responses in LC-NA neurons, they modulate pain thresholds and depression-like behaviors in a manner independent of LC-NA neurons. In contrast, the projection from LC-GABA neurons to the ventrolateral periaqueductal gray (vlPAG) is enhanced, and stimulation of this projection mimics that of LC-GABA neurons conferring analgesic- and antidepressant-like effects. This study reveals the enhancement of the LC-vlPAG projection as a compensatory mechanism in neuropathic pain and suggests that further augmentation of this projection may be a therapeutic strategy for the treatment of comorbid neuropathic pain and depression.
蓝斑（LC）去甲肾上腺素能（NA）神经元通过其向各种下游核团的投射来调节疼痛和抑郁。尽管LC及其附近的γ-氨基丁酸能（GABA）神经元（LC-GABA神经元）为LC-NA神经元提供抑制性突触输入，但它们是否通过LC-NA神经元参与神经性疼痛和共病性抑郁仍不清楚。本研究表明，LC-GABA神经元对有害刺激的反应是活性增强，刺激这些神经元可提高疼痛阈值，并在未患神经性疼痛的小鼠和患神经性疼痛的小鼠中发挥类似抗抑郁的作用。相反，抑制LC-GABA神经元会导致未患神经性疼痛的小鼠出现痛觉过敏和类似抑郁的行为，并加剧患神经性疼痛的小鼠现有的疼痛和类似抑郁的行为。尽管LC-GABA神经元抑制LC-NA神经元的疼痛反应，但它们以独立于LC-NA神经元的方式调节疼痛阈值和类似抑郁的行为。相比之下，LC-GABA神经元向腹外侧导水管周围灰质（vlPAG）的投射增强，刺激该投射可模拟LC-GABA神经元的作用，产生镇痛和抗抑郁样效果。本研究揭示了LC-vlPAG投射增强是神经性疼痛中的一种代偿机制，并表明进一步增强该投射可能是治疗共病性神经性疼痛和抑郁的一种治疗策略。
