Divergent Opioidergic Brainstem Pathways that Mediate Pain-Breathing Interaction

Breathing and pain perception seem to be unrelated critical brain functions, yet they influence each other. Severe pain induces hyperventilation, whereas paced slow breathing alleviates pain perception. However, a neural circuit-based understanding of pain-breathing interaction is lacking. Here we report that Oprm1 (µ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for regulating breathing, pain, and their interaction. The PBL Oprm1 activity is tightly correlated with the breathing rhythm, and noxious stimuli simultaneously elevate both. Manipulating PBL Oprm1 activity collectively modulates breathing rhythm and negative affects, such as pain and anxiety. Furthermore, we find that the association of pain and breathing is mediated by two non-overlapping but reciprocally connected Oprm1 subpopulations in the core and shell of the PBL, which diverge to the central amygdala and medullary respiratory center, respectively. These results uncover the role of the parabrachial opioidergic pathways in regulating basal respiratory rhythm and pain-breathing interaction.