A craniofacial-specific monosynaptic circuit enables heightened affective pain

Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PB L ), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PB L neurons and performed comprehensive anatomical input–output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PB L -nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PB L projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain. The authors show that unlike body sensory neurons, craniofacial nociceptive neurons directly synapse with noxious-stimulus-activated lateral parabrachial neurons (PB L ), which in turn project to multiple limbic centers processing emotions and affects. This monosynaptic pathway is both sufficient and necessary for craniofacial-pain-activated aversive behaviors.