Medial prefrontal cortex and ventrolateral orbitofrontal cortex inputs into the ventrolateral periaqueductal grey region differentially regulate pain and anxiety like behavior.

Distinct cortical inputs to the ventrolateral periaqueductal gray (vlPAG) have been implicated in pain modulation, however, the effect of their simultaneous activation on pain and anxiety remains unclear. Here, we examined the roles of medial prefrontal cortex (mPFC) and ventrolateral orbitofrontal cortex (vlOFC) projections to the vlPAG in a neuropathic pain model. Using optogenetic stimulation in spared nerve injury (SNI) mice, activation of either mPFC or vlOFC inputs to the vlPAG partially reduced mechanical hypersensitivity, whereas simultaneous activation produced a complete analgesic effect. c-Fos analysis revealed increased neuronal activation across all conditions following activation of the respective circuits, with glutamatergic neurons predominating over GABAergic neurons within the c-Fos + population. Anatomical tracing showed that mPFC and vlOFC projections target distinct subregions within the vlPAG. In addition, the mPFC-vlPAG pathway appears to primarily drive the anxiolytic effect. These findings demonstrate that mPFC and vlOFC inputs to the vlPAG differentially regulate pain and anxiety related behaviors and provide new insight into cortical control of these processes.