Pain arises from the integration of sensory and affective processes, but how aversive states modulate pain sensitivity remains unclear. Here, we identify a descending medial prefrontal cortex–parabrachial nucleus (mPFC–PBN) pathway that links aversive states to pain hypersensitivity. Retrograde tracing and slice electrophysiology reveal functional excitatory mPFC input to PBN neurons that is strengthened after spared nerve injury (SNI).
Molecular profiling shows that mPFC-recipient PBN neurons are mainly Slc17a6/Vglut2-positive, with a prominent Tacr1-expressing subpopulation. Single-cell calcium imaging reveals responses to nociceptive stimuli and aversive sound, with increased sound-evoked recruitment after SNI. Behaviorally, aversive sound induces anxiety-like behavior and mechanical/thermal hypersensitivity, both attenuated by optogenetic inhibition of the mPFC–PBN projection.
Conversely, pathway activation recapitulates these effects, whereas pathway inhibition alleviates SNI-induced anxiety-like behavior and hypersensitivity. These findings identify mPFC–PBN signaling as a descending cortical–brainstem mechanism contributing to pain–anxiety comorbidity. This work was supported by Guangdong S&T Program (2023B0303010002), Guangdong Basic and Applied Basic Research Foundation (2023B1515020099), Technological Innovation 2030-Major Projects of “Brain Science and Brain-like Research” (2022ZD0206200 and 2025ZD0214902), and the National Natural Science Foundation of China (32371052).
Department of Biology, Faculty of Arts and Sciences, Beijing Normal University at Zhuhai, Zhuhai, Guangdong, China Zai-Yong An, Xiao-Mei Yang, Ya-Xuan Liang & Di Mu Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong, China Zai-Yong An, Xiao-Mei Yang, Meng-Yao Song, Ming-Zhe Liu & Di Mu Correspondence to Ya-Xuan Liang or Di Mu. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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