Identification of a novel breathing circuit that controls pain and anxiety

Abstract Alleviating pain with controlled breathing has been practiced throughout human history. Despite its wide use and long history, a neural circuit-based understanding of the pain-breathing interaction is largely lacking. Here we report a novel breathing circuit that regulates non-homeostatic breathing rhythm, as well as pain and anxiety. We identify that a cluster of neurons expressing the Oprm1 gene, which encodes the μ-opioid receptor (MOR) in the lateral subdivision of parabrachial nucleus (PBL Oprm1 ), directly regulates breathing rate in mice by conveying signals from the limbic areas to respiratory rhythm generating neurons in the medullary preBötzinger Complex (preBötC). In addition, we found that pain signals rapidly increase breathing rate by activating these neurons in both awake and anesthetized mice. Inactivating these neurons not only decreases the breathing rate, but it also substantially decreases anxiety-like behaviors and induces strong appetitive behaviors. Furthermore, PBL Oprm1 inactivation alleviates pain by attenuating the perception of the affective-motivational aspect of pain. These results suggest that PBL Oprm1 neurons play a critical role in the non-homeostatic regulation of breathing and in the regulation of pain and anxiety through breathing.