How pain and anxiety impact breathing on a cellular level

We’ve all experienced an increase in our breathing rate when we’re hurting or anxious, but exactly why this happens was not previously understood. Scientists at the Salk Institute for Biological Studies have now uncovered a neural network in the brain that coordinates breathing rhythm with feelings of pain and fear — and their results, published in the journal Neuron, could lead to development of an analgesic that would prevent the disrupted breathing that causes opioid overdose deaths.

Researchers in the lab of Assistant Professor Sung Han focused on a group of neurons in the brainstem called the lateral parabrachial nucleus, which is arranged in a core-shell configuration. They found that neurons in the core project to the amygdala, an area of the brain that processes fear and the emotional experience of pain. Neurons in the shell project to the pre-Bötzinger complex, a region that generates breathing rhythm. The core and shell neurons influence each other according to inputs from these areas, making us breathe faster when we experience pain or anxiety.

Shell neurons (green) project to the breathing centre and core neurons (red) project to the pain/emotion centre. Image credit: Salk Institute.

In opioid-induced respiratory depression (OIRD), opioids repress breathing as well as pain, which can result in death. In previous work, Asst Prof Han’s team showed that opiates like morphine repress breathing by triggering specific receptors, called mu opioid receptors (MOR), leading to the inhibition of neurons that express them. They also showed that reactivating the cells that express MOR can reverse OIRD. The current work suggests additional approaches for preventing OIRD, possibly by inhibiting neurons in the region’s core (blunting fear/anxiety) while exciting similar neurons in the shell (supporting breathing).

To show how these neurons coordinate breathing with pain and emotions, the researchers first used light and chemical agents to prove that manipulating the MOR-expressing neurons in the lateral parabrachial nucleus alters breathing rate in mice. They then used fluorescent tracers to map the inputs and outputs to the MOR-expressing neurons. Their results indicated that neurons clustered in the core of the region project to the central amygdala, while neurons clustered in the surrounding shell project to the pre-Bötzinger complex. Electrophysiological recordings of one population while stimulating the other population revealed that some of those subpopulations are reciprocally connected, with an excitatory network between them. Via this network, signals of fear and pain were coordinated with breathing rhythms.

“We have found very intricate circuits involving upstream and downstream input to these neurons,” said first author Shijia Liu, a graduate student in Asst Prof Han’s. “By uncovering this circuit mechanism, we can better explain why breathing can often be coordinated with pain and anxiety.”

Asst Prof Han is particularly eager to see the team’s discovery have a translational application, noting, “The biggest problem these days is that opioids reduce pain but also reduce breathing, so people die. By understanding those two mechanisms in our research, maybe we can manipulate certain populations of neurons by pharmacological intervention so that we can control pain without changing the breathing.”

Top image credit: ©stock.adobe.com/au/LIGHTFIELD STUDIOS

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