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.

Neural basis of opioid-induced respiratory depression and its rescue

“…2 N and Q). The opposite effects on locomotion and calcium activity observed after morphine administration demonstrated that the breathing-associated fluctuation of PBL Oprm1 activity is not affected by the movement, which is further demonstrated in our concurrent independent study (39). In contrast, saline injection largely preserved the original patterns of the signals (Fig.…”

“…In our view, OIRD is a synergistic outcome from impairment of the interconnected pontomedullary breathing network that widely expresses MOR both pre-and postsynaptically (15,16,35,51,52). For example, parabrachial neurons send tonic excitatory inputs to the preBötC (39,47,53,54), and both of these areas express MOR (23,55). Besides, the preBӧtC, as the breathing pattern generator, has been known to contribute to the OIRD phenotype, yet the level of its involvement varies across species and overdose models.…”

Neural basis of opioid-induced respiratory depression and its rescue

“…In our view, OIRD is a synergistic outcome from impairment of the interconnected pontomedullary breathing network that widely expresses MOR both pre-and post-synaptically (10,11,30,44,45). For example, parabrachial neurons send tonic excitatory inputs to the preBötC (39,43,46,47), and both of these areas express MOR (18,48).…”

“…Indeed, the incidence of OIRD is dramatically increased when opioids are used together with sedatives and anesthetics (52), and the failure to increase respiratory behavior in response to hypercapnic gas is one characteristic of OIRD (3). On the contrary, a mild inhibition of PBL Oprm1 neurons may explain many of the behavioral effects of lower doses of endogenous or exogenous opioids, such as slowed breathing, calmness, and reward (43). The current study used morphine as a starting point to induce OIRD, and further investigation is required to determine the involvement of PBL Oprm1 neurons under the challenge of other types of sedative agents.…”

“…In addition to breathing, the PBL also regulates various homeostatic functions (39) and incorporates the alarm center, which senses deviations from the homeostasis and relays aversive signals to higher-order brain structures (38,50). At the same time, by sending tonic excitatory outputs to medulla respiratory centers (39,43,46), the parabrachial neurons can increase breathing rhythm under conditions that immediately require more oxygen due to metabolic needs, such as hypoxia (27) and hypercapnia (26), in particular, hypercapnic arousal during sleep (24,28,51); or non-metabolic behavioral demands, such as escaping from a threat (25). As a representative glutamatergic population in the PBL (Supplementary Figure 1), Oprm1-positive neurons are likely to participate in similar physiological processes.…”