Norepinephrinergic projection from locus coeruleus to parafascicular nucleus promotes pain and anxiety-like behaviors in mice

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Abstract

Chronic neuropathic pain is frequently comorbid with anxiety disorders, yet the neural circuits underlying this interaction remain poorly defined. The parafascicular nucleus (PF) of the thalamus integrates nociceptive and affective signals, but its specific regulatory mechanisms in pain-anxiety comorbidity are not well known. Using spared nerve injury (SNI) model mice, we combined viral neural tracing, chemogenetics, pharmacology, and electrophysiology to dissect the locus coeruleus (LC)–PF neural pathway. Viral tracing revealed monosynaptic projections from norepinephrinergic (NEergic) neurons in the dorsal LC to Ca2+/calmodulin–dependent protein kinase IIα–immunopositive (CaMKIIα+) neurons within the PF. Chemogenetic inhibition and activation of this pathway were performed in naive and SNI mice, alongside intra-PF microinjection of the α-2 adrenergic receptor (ADRA2) antagonist yohimbine. Behavioral tests assessed mechanical/thermal hypersensitivity and anxiety-like behaviors. Results showed that 92.1% of PF-projecting LC neurons were NEergic, with 70.1% localized dorsally. Chemogenetic inhibition of the LCNE-PFCaMKIIα neural pathway significantly alleviated both acute-phase mechanical hypersensitivity (<7 days after surgery) and chronic-phase anxiety-like behaviors in SNI mice, while activation of this pathway induced pain sensitization and anxiety-like behaviors in naive mice. Intra-PF yohimbine reversed SNI-induced allodynia and anxiety-like behaviors. Electrophysiology confirmed that yohimbine increased PF neuronal intrinsic excitability. These results suggest that the LCNE-PFCaMKIIα neural pathway promotes neuropathic pain and comorbid anxiety via ADRA2-mediated suppression of PF neuronal activity. Targeted inhibition of this circuit may represent a therapeutic strategy for pain-related affective disorders.

Authors

Zhong-Yi Liu, Fei Li, Li-Ming Liu, Yao-Hua Liu, Jia Li, Zi-Ang Li, Jin Cheng, Tian-Yu Zhao, Hui-Min Tian, Dong-Ning Li, Sha-Sha Tao, Hui Li, Fen-Sheng Huang, Yun-Qing Li