We have all had the experience of gasping out loud when we hurt ourselves, or breathing faster when we get a fright. But the reason why our breathing rate increases when we are anxious or in pain was not previously understood.
In recent research, however, a team of scientists from the Salk Institute has found that a neural network in the brain coordinates breathing rhythm with feelings of pain and fear. They propose that this finding could lead to the development of an analgesic that would prevent opioid-induced respiratory depression (OIRD), the disrupted breathing that can cause death in those who overdose on opioid drugs.
Opioid medications are often used as painkillers, and they are effective at reducing pain. However, they also reduce breathing rate, sometimes to the extent that the user stops breathing and dies. There was clearly a need to understand the mechanism whereby breathing rate is coordinated with the experience of pain.
In the study, published today in the journal Neuron, the Salk scientists focused on a group of neurons in the brainstem called the lateral parabrachial nucleus. Nerve cells in this region are arranged in the form of a core, which is surrounded by a shell. They found that, whereas 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.
“We are the first group to demonstrate how the lateral parabrachial nucleus coordinates breathing and pain,” said study senior author Professor Sung Han. “By understanding the circuits in this brain region, we may be able to tease apart breathing regulation and pain regulation to develop a medication that inhibits feelings of pain without repressing breathing, like OIRD.”
Researchers in Professor Han’s lab had previously shown that opiates like morphine repress breathing by triggering specific receptors, called mu opioid receptors (MORs). This leads to the inhibition of neurons that express these receptors. They also showed that reactivating the cells that express MORs can reverse OIRD. Their current research suggests there may be different approaches to preventing OIRD, possibly by inhibiting neurons in the region’s core (blunting fear/anxiety) while exciting similar neurons in the shell (supporting breathing).
In order to show how the core and shell 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.
The results showed that nerve cells in the core project to the central amygdala, while neurons clustered in the surrounding shell project to the pre-Bötzinger complex. When they recorded electrical activity in neurons from one of the regions (core or shell), while stimulating activity in the other region, they found that the two groups of nerve cells were connected to one another by means of an excitatory network of neurons. It is through this network that signals of fear and pain are coordinated with breathing rhythm.
“We have found very intricate circuits involving upstream and downstream input to these neurons. By uncovering this circuit mechanism, we can better explain why breathing can often be coordinated with pain and anxiety,” said first author Shijia Liu, a graduate student in Han’s lab.
Professor Han is eager to see the team’s discovery have a functional application. “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.”
The researchers in Han’s group are now undertaking genetic analyses of the core and shell neurons to identify specific functional markers that regulate pain or breathing.