The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice
Abstract Background The neuronal activities within the dorsal raphe nucleus (DRN) and the ventrolateral orbital cortex (VLO) are strongly implicated in the development of depression, a condition comorbid with chronic pain. The goal of the present study was to determine whether and how the DRN-VLO pa...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | The Journal of Headache and Pain |
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| Online Access: | https://doi.org/10.1186/s10194-025-02110-3 |
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| author | Hai-Yan Sheng Wei-Zhen Liu Yan-Kai Liu Qing-Rong Han Dong-Yang Chen Li-Bin Zhang Xin-Ru Chu Si-Han He Jia-Xin Li Zi-Qing Zhang Bo-Han Duanmu Ya-Ling Yin Lin-Hua Jiang |
| author_facet | Hai-Yan Sheng Wei-Zhen Liu Yan-Kai Liu Qing-Rong Han Dong-Yang Chen Li-Bin Zhang Xin-Ru Chu Si-Han He Jia-Xin Li Zi-Qing Zhang Bo-Han Duanmu Ya-Ling Yin Lin-Hua Jiang |
| author_sort | Hai-Yan Sheng |
| collection | DOAJ |
| description | Abstract Background The neuronal activities within the dorsal raphe nucleus (DRN) and the ventrolateral orbital cortex (VLO) are strongly implicated in the development of depression, a condition comorbid with chronic pain. The goal of the present study was to determine whether and how the DRN-VLO pathway mediates chronic pain-induced depression. Methods Trigeminal neuralgia was induced unilaterally by chronic constriction injury of the infraorbital nerve. Depressive-like behaviors were assessed by the open field test, forced swimming test and tail suspension test. Neuronal projection tracing, chemogenetic manipulations and pharmacological interventions were performed to determine the DRN-VLO pathway projection activity and pathway-mediated anti-depressant mechanism in mice with trigeminal neuralgia. The neuronal activity was assessed by measuring the c-Fos level using immunofluorescence imaging. Results The VLO receives direct projection of the serotonergic neurons from the DRN. Anterograde or retrograde activation of the DRN-VLO pathway consistently produced anti-depressant effects in mice with neuropathic pain, whereas sustained inhibition of this pathway in healthy mice induced depressive-like behaviors. Activation of the 5-HT1A or 5-HT2A receptor in the VLO produced anti-depressant effects. Activation of the GABAA receptors in the VLO weakened 5-HT1A receptor-mediated anti-depressant effect. Conclusions The present study has revealed that activation of the DRN-VLO pathway exerts an anti-depressant effect in mice with neuropathic pain, through stimulating the 5-HT2A receptors in the excitatory neurons and also the 5-HT1A receptors in the GABAergic interneurons via a dis-inhibition mechanism, to enhance neuronal activity of the VLO. |
| format | Article |
| id | doaj-art-46ed83e4d25a403bbd5d2a31990cec73 |
| institution | Kabale University |
| issn | 1129-2377 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | The Journal of Headache and Pain |
| spelling | doaj-art-46ed83e4d25a403bbd5d2a31990cec732025-08-20T03:46:25ZengBMCThe Journal of Headache and Pain1129-23772025-07-0126111710.1186/s10194-025-02110-3The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in miceHai-Yan Sheng0Wei-Zhen Liu1Yan-Kai Liu2Qing-Rong Han3Dong-Yang Chen4Li-Bin Zhang5Xin-Ru Chu6Si-Han He7Jia-Xin Li8Zi-Qing Zhang9Bo-Han Duanmu10Ya-Ling Yin11Lin-Hua Jiang12Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversitySino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical UniversityAbstract Background The neuronal activities within the dorsal raphe nucleus (DRN) and the ventrolateral orbital cortex (VLO) are strongly implicated in the development of depression, a condition comorbid with chronic pain. The goal of the present study was to determine whether and how the DRN-VLO pathway mediates chronic pain-induced depression. Methods Trigeminal neuralgia was induced unilaterally by chronic constriction injury of the infraorbital nerve. Depressive-like behaviors were assessed by the open field test, forced swimming test and tail suspension test. Neuronal projection tracing, chemogenetic manipulations and pharmacological interventions were performed to determine the DRN-VLO pathway projection activity and pathway-mediated anti-depressant mechanism in mice with trigeminal neuralgia. The neuronal activity was assessed by measuring the c-Fos level using immunofluorescence imaging. Results The VLO receives direct projection of the serotonergic neurons from the DRN. Anterograde or retrograde activation of the DRN-VLO pathway consistently produced anti-depressant effects in mice with neuropathic pain, whereas sustained inhibition of this pathway in healthy mice induced depressive-like behaviors. Activation of the 5-HT1A or 5-HT2A receptor in the VLO produced anti-depressant effects. Activation of the GABAA receptors in the VLO weakened 5-HT1A receptor-mediated anti-depressant effect. Conclusions The present study has revealed that activation of the DRN-VLO pathway exerts an anti-depressant effect in mice with neuropathic pain, through stimulating the 5-HT2A receptors in the excitatory neurons and also the 5-HT1A receptors in the GABAergic interneurons via a dis-inhibition mechanism, to enhance neuronal activity of the VLO.https://doi.org/10.1186/s10194-025-02110-3Neuropathic painDepressionDRN-VLO pathway5-HT1A/5-HT2A receptorsGABAA receptor |
| spellingShingle | Hai-Yan Sheng Wei-Zhen Liu Yan-Kai Liu Qing-Rong Han Dong-Yang Chen Li-Bin Zhang Xin-Ru Chu Si-Han He Jia-Xin Li Zi-Qing Zhang Bo-Han Duanmu Ya-Ling Yin Lin-Hua Jiang The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice The Journal of Headache and Pain Neuropathic pain Depression DRN-VLO pathway 5-HT1A/5-HT2A receptors GABAA receptor |
| title | The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice |
| title_full | The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice |
| title_fullStr | The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice |
| title_full_unstemmed | The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice |
| title_short | The DRN-VLO pathway via distinct 5-HT synaptic mechanisms modulates neuropathic pain–induced depressive-like behaviors in mice |
| title_sort | drn vlo pathway via distinct 5 ht synaptic mechanisms modulates neuropathic pain induced depressive like behaviors in mice |
| topic | Neuropathic pain Depression DRN-VLO pathway 5-HT1A/5-HT2A receptors GABAA receptor |
| url | https://doi.org/10.1186/s10194-025-02110-3 |
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