Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses
Abstract Background Mu-opioid receptors (MORs) are critical regulators mediating the modulation of several behavioral reactions, including analgesia, addiction, and sedation. Recent studies have reported that MORs are closely associated with mood disorders or anxiety behaviors; however, the underlyi...
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BMC
2025-07-01
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| Series: | Behavioral and Brain Functions |
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| Online Access: | https://doi.org/10.1186/s12993-025-00291-0 |
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| author | Yinan Du Aozhuo Zhang Zhiwei Li Yukui Zhao Shuyi Liu Chunling Wei Qiaohua Zheng Yanning Qiao Yihui Liu Wei Ren Jing Han Zhiqiang Liu Fei Gao |
| author_facet | Yinan Du Aozhuo Zhang Zhiwei Li Yukui Zhao Shuyi Liu Chunling Wei Qiaohua Zheng Yanning Qiao Yihui Liu Wei Ren Jing Han Zhiqiang Liu Fei Gao |
| author_sort | Yinan Du |
| collection | DOAJ |
| description | Abstract Background Mu-opioid receptors (MORs) are critical regulators mediating the modulation of several behavioral reactions, including analgesia, addiction, and sedation. Recent studies have reported that MORs are closely associated with mood disorders or anxiety behaviors; however, the underlying neural mechanisms remain unclear. The periaqueductal gray (PAG), a key brain area, participates in the modulation of aversive emotional behaviors. MORs show a high expression in the ventrolateral PAG (vlPAG) region. This study explored the preliminary role of MORs expressed in the vlPAG in modulating emotional behaviors. Results Bilateral administration of DAMGO, an MOR-specific agonist, into the vlPAG of male mice elicited anxiety-like behaviors in elevated plus maze tests. This phenotype was reversed by conditional knockdown of astrocytic MORs. In contrast, glutamatergic or GABAergic MORs were not involved in vlPAG MOR-dependent anxiety-like behaviors. By using in vitro calcium imaging of vlPAG astrocytes and chemical genetic technologies, we found that vlPAG astrocytic MORs can promote astrocytic calcium signaling, which can efficiently induce anxiety-like behaviors. Accordingly, the interference of astrocytic calcium signaling by viral infection reversed vlPAG-dependent anxiety-like behaviors. Conclusion Our findings demonstrated that vlPAG astrocytic, but not glutamatergic or GABAergic, MORs are involved in modulating emotional reactions, and these effects are accomplished by MOR-elicited astrocytic calcium signaling mechanisms. The present study provides a theoretical basis for treating emotional dysfunctions during MOR-targeted management. |
| format | Article |
| id | doaj-art-192c74a6ce43403ebd87d186e38654bd |
| institution | Kabale University |
| issn | 1744-9081 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Behavioral and Brain Functions |
| spelling | doaj-art-192c74a6ce43403ebd87d186e38654bd2025-08-20T03:46:25ZengBMCBehavioral and Brain Functions1744-90812025-07-0121111510.1186/s12993-025-00291-0Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responsesYinan Du0Aozhuo Zhang1Zhiwei Li2Yukui Zhao3Shuyi Liu4Chunling Wei5Qiaohua Zheng6Yanning Qiao7Yihui Liu8Wei Ren9Jing Han10Zhiqiang Liu11Fei Gao12Department of Neurology, The First Affiliated Hospital of Xi’an Medical UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityMOE Key Laboratory of Modern Teaching Technology, Shaanxi Normal UniversityDepartment of Neurology, The First Affiliated Hospital of Xi’an Medical UniversityAbstract Background Mu-opioid receptors (MORs) are critical regulators mediating the modulation of several behavioral reactions, including analgesia, addiction, and sedation. Recent studies have reported that MORs are closely associated with mood disorders or anxiety behaviors; however, the underlying neural mechanisms remain unclear. The periaqueductal gray (PAG), a key brain area, participates in the modulation of aversive emotional behaviors. MORs show a high expression in the ventrolateral PAG (vlPAG) region. This study explored the preliminary role of MORs expressed in the vlPAG in modulating emotional behaviors. Results Bilateral administration of DAMGO, an MOR-specific agonist, into the vlPAG of male mice elicited anxiety-like behaviors in elevated plus maze tests. This phenotype was reversed by conditional knockdown of astrocytic MORs. In contrast, glutamatergic or GABAergic MORs were not involved in vlPAG MOR-dependent anxiety-like behaviors. By using in vitro calcium imaging of vlPAG astrocytes and chemical genetic technologies, we found that vlPAG astrocytic MORs can promote astrocytic calcium signaling, which can efficiently induce anxiety-like behaviors. Accordingly, the interference of astrocytic calcium signaling by viral infection reversed vlPAG-dependent anxiety-like behaviors. Conclusion Our findings demonstrated that vlPAG astrocytic, but not glutamatergic or GABAergic, MORs are involved in modulating emotional reactions, and these effects are accomplished by MOR-elicited astrocytic calcium signaling mechanisms. The present study provides a theoretical basis for treating emotional dysfunctions during MOR-targeted management.https://doi.org/10.1186/s12993-025-00291-0AnxietyMu-opioid receptorsPeriaqueductal grayAstrocyteCalcium signaling |
| spellingShingle | Yinan Du Aozhuo Zhang Zhiwei Li Yukui Zhao Shuyi Liu Chunling Wei Qiaohua Zheng Yanning Qiao Yihui Liu Wei Ren Jing Han Zhiqiang Liu Fei Gao Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses Behavioral and Brain Functions Anxiety Mu-opioid receptors Periaqueductal gray Astrocyte Calcium signaling |
| title | Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses |
| title_full | Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses |
| title_fullStr | Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses |
| title_full_unstemmed | Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses |
| title_short | Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses |
| title_sort | role of astrocytic mu opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety like responses |
| topic | Anxiety Mu-opioid receptors Periaqueductal gray Astrocyte Calcium signaling |
| url | https://doi.org/10.1186/s12993-025-00291-0 |
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