Five Things to Know About How Orexin Affects Stress Resilience

What’s going on inside our bodies and brains when we respond to stress? Previously, we covered research into powerful little neuropeptides called orexins that may help regulate an individual’s vulnerability to stress. Now, we dug into fresh research from the lab of Seema Bhatnagar, PhD, an associate professor in the division of Stress Neurobiology at Children’s Hospital of Philadelphia, and conducted by Laura Grafe, PhD, a postdoctoral fellow. Dr. Grafe studies how orexins regulate behavioral and neuroendocrine responses to repeated stress. (Or, in other words, how animals behave when exposed to a stressor multiple times.) The exciting research of Dr. Grafe and her colleagues appeared recently in Neuroscience. When we chatted with Drs. Bhatnagar and Grafe, we learned five fascinating facts about how orexin can affect an individual’s stress response – and what that might mean about building resilience.

Orexins increase arousal and can affect sleep, binge-eating, and habituation to stress.

Orexin is a neuropeptide that’s been associated with sleep, appetite, and more recently, stress. It’s known to mediate arousal and alertness in the body. In the case of sleep, blocking orexins can help to combat insomnia, while too little orexin can cause narcolepsy. In the case of stress, high orexin levels have been linked with a higher stress response.

“We know that with a single stressor, if you block orexins, you reduce the stress response,” Dr. Grafe said.

In the new study, however, she and her colleagues looked into a lesser-known aspect of the phenomenon: How orexins might be involved in the habituation to repeated stress – or what Bhatnagar describes as a “decreased response to a familiar stress that you have been exposed to over and over again.” A simplified example might be a freshman college student becoming acclimated to the onslaught of exams and homework and, with experience, finding they don’t get as flustered.

Orexin levels drop over a period of repeated stress.

Dr. Grafe and her fellow researchers conducted a restraint test with rats: For 30 minutes a day, five days in a row, they limited the rat’s physical movement to study how the animals struggled in response. They then measured their orexin levels in the brain.

“We found that by measuring levels of orexin in the cerebrospinal fluid and the activation of orexin neurons, both of these decreased over the five days of repeated stress,” Dr. Grafe said.

The finding shows that orexin levels do indeed fluctuate as the rats habituate or adapt to repeated stress – and that orexin may even play a key role in that habituation. While this was fascinating in itself, the researchers wanted to know how and why exactly this happens, and also what might happen under conditions of extreme stress, as seen in panic disorders. Learning the mechanisms behind a decrease in orexin can help researchers design treatments to mimic that process.

Blocking the orexin 2 receptor decreases stress levels for just day one.

Orexin has two receptors: orexin 1 and orexin 2. As with all receptors, different receptors can produce different effects when attached to a respective chemical. Using an orexin receptor antagonist, the researchers blocked the actions of orexin 2 over the course of the five days of stress to see whether stress levels still decreased in the absence of the chemical’s second receptor. From their observations, they found that orexin 2 receptor did appear to regulate the rat’s stress levels – but only on day one. One possible hypothesis: Orexin 1 receptor may play a larger role in the course of five days of repeated stress.

In a hyperactive state of stress, however, blocking the orexin 2 receptor decreases stress levels.

As part of the study, the researchers also wanted to create models of extremely high stress responses, such as panic disorder, to study how blocking orexin receptors might help with that.

“What’s interesting is that with certain disease states like panic disorder, orexins are highly stimulated, and levels are much higher with those types of disorders,” Dr. Grafe said. “So what we wanted to do was model this.”

They used DREADDS technology (which stands for designer receptors exclusively activated by designer drugs) to stimulate the rat’s orexin neurons and release more orexins. In other words, the rats were incredibly stressed out.

“We did this throughout the repeated stress to see what would happen in that hyperactive state of orexin activation,” Dr. Grafe said.

They found that orexin 2 now appeared to play a role in five days of stress – not just one – during this overstimulated state.

We can’t translate rat studies to human application just yet, but that’s the direction researchers hope to travel toward.

While it’s tempting to make the connection between a rat’s behavior when put under restraint and our own resilience during our days of high pressure, we can’t exactly translate a rodent study into immediate human conclusions. Nevertheless, the researchers have their hypotheses.

“What you can sort of hypothesize is that in somebody with panic disorder, where orexins are overstimulated, perhaps orexins are regulating their response to repeated stress,” Dr. Grafe said.

Future drugs may even be developed to block the actions of orexin 2, as Dr. Grafe did in the study, to soothe an aggressive stress response in the body. In current and upcoming research, Drs. Bhatnagar and Grafe will dig deeper into the link between orexins and vulnerability, and piece their discoveries together with other lab work on the neurobiology of stress resilience.