Role of astrocytic mu-opioid receptors of the ventrolateral periaqueductal gray in modulating anxiety-like responses

• Published in: Behavioral and brain functions Vol. 21; no. 1; pp. 24 - 15
• Main Authors: Du, Yinan, Zhang, Aozhuo, Li, Zhiwei, Zhao, Yukui, Liu, Shuyi, Wei, Chunling, Zheng, Qiaohua, Qiao, Yanning, Liu, Yihui, Ren, Wei, Han, Jing, Liu, Zhiqiang, Gao, Fei
• Format: Journal Article
• Language: English
• Published: England BioMed Central 23.07.2025; BMC
• Subjects: Addictions; Amygdala; Analgesia; Analgesics, Opioid - pharmacology; Animals; Anxiety; Anxiety - metabolism; Astrocyte; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Behavior; Brain; Calcium imaging; Calcium signaling; Calcium Signaling - drug effects; Calcium Signaling - physiology; Calcium signalling; Emotional behavior; Enkephalin, Ala-MePhe-Gly- - pharmacology; Enkephalins; Glutamatergic transmission; Infusion pumps; Male; Mice; Mice, Inbred C57BL; Mu-opioid receptors; Narcotics; Neuroimaging; Opioid receptors (type mu); Periaqueductal gray; Periaqueductal Gray - drug effects; Periaqueductal Gray - metabolism; Periaqueductal gray area; Phenotypes; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Surgery; γ-Aminobutyric acid; China; Calcium signaling; Periaqueductal gray; Anxiety; Astrocyte; Mu-opioid receptors
• ISSN: 1744-9081; 1744-9081
• DOI: 10.1186/s12993-025-00291-0

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. 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. 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.