The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression
Abstract 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 the...
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202503739 |
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| author | Yuan Gao Xue Zhang Xiao‐Juan Liu Yi‐Ling Sun Cui Yin Dong‐Liang Tang Cheng Xiao Chunyi Zhou |
| author_facet | Yuan Gao Xue Zhang Xiao‐Juan Liu Yi‐Ling Sun Cui Yin Dong‐Liang Tang Cheng Xiao Chunyi Zhou |
| author_sort | Yuan Gao |
| collection | DOAJ |
| description | Abstract 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 LCGABA‐vlPAGGABA 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. |
| format | Article |
| id | doaj-art-6860b8aeb23240798060f39b7b9bc5ed |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
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| spelling | doaj-art-6860b8aeb23240798060f39b7b9bc5ed2025-08-20T04:01:01ZengWileyAdvanced Science2198-38442025-07-011226n/an/a10.1002/advs.202503739The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and DepressionYuan Gao0Xue Zhang1Xiao‐Juan Liu2Yi‐Ling Sun3Cui Yin4Dong‐Liang Tang5Cheng Xiao6Chunyi Zhou7Jiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaDepartment of Anesthesiology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School, Nanjing University Nanjing Jiangsu 210008 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaJiangsu Province Key Laboratory of Anesthesiology School of Anesthesiology Xuzhou Medical University Xuzhou Jiangsu 221004 ChinaAbstract 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 LCGABA‐vlPAGGABA 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.https://doi.org/10.1002/advs.202503739depressionGABAergic neuronlocus coeruleusneuropathic painnoradrenergic neuronventrolateral periaqueductal gray |
| spellingShingle | Yuan Gao Xue Zhang Xiao‐Juan Liu Yi‐Ling Sun Cui Yin Dong‐Liang Tang Cheng Xiao Chunyi Zhou The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression Advanced Science depression GABAergic neuron locus coeruleus neuropathic pain noradrenergic neuron ventrolateral periaqueductal gray |
| title | The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression |
| title_full | The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression |
| title_fullStr | The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression |
| title_full_unstemmed | The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression |
| title_short | The Locus Coeruleus‐Periaqueductal Gray GABAergic Projection Regulates Comorbid Pain and Depression |
| title_sort | locus coeruleus periaqueductal gray gabaergic projection regulates comorbid pain and depression |
| topic | depression GABAergic neuron locus coeruleus neuropathic pain noradrenergic neuron ventrolateral periaqueductal gray |
| url | https://doi.org/10.1002/advs.202503739 |
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