A descending cortical–brainstem pathway links emotional state to pain sensitivity

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 study uses tracing, electrophysiology, calcium imaging, and circuit manipulation to examine a medial prefrontal cortex to parabrachial nucleus pathway in mouse pain models. The pathway links aversive states to pain hypersensitivity and contributes to pain-anxiety comorbidity.