Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions

Neuron. 2021 Dec 15;S0896-6273(21)00990-9. doi: 10.1016/j.neuron.2021.11.029. | PubMed

Shijia Liu¹, Mao Ye², Gerald M Pao³, Samuel M Song⁴, Jinho Jhang², Haibei Jiang⁴, Jong-Hyun Kim², Sukjae J Kang², Dong-Il Kim², Sung Han⁵

1. Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
2. Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3. Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4. Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
5. Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: sunghan@salk.edu.

Abstract

Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (μ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBLOprm1 neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBLOprm1 activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBLOprm1 neurons constitute two distinct subpopulations in a "core-shell" configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing.

Presented By Shijia Liu } ORCID iD