University of Minnesota
Hearts and other muscles have a special way of producing pain signals when they're deprived of oxygen.
Why heart attacks hurt
How oxygen-starved muscles signal their distress
By Deane Morrison
It happens to heart attack sufferers and highly fit marathoners alike. When a muscle isn't getting enough oxygen, it hurts.
Yet while the pain is caused by lactic acid leaking from oxygen-stressed muscle, the amounts of acid are too low for pain nerves in muscle to detect.
That paradox led University of Minnesota neuroscientist Robert Elde and his colleagues at the U of M and Oregon Health and Sciences University to investigate how oxygen-starved muscles get their SOS through to the nervous system.
"We're on a quest to understand many, if not all, types of pain," explains Elde, who is also dean of the College of Biological Sciences. "It's part of a strategy for developing new ways to eliminate pain."
Getting to the root of pain due to insufficient oxygen—called ischemic pain—has obvious implications for heart attack patients and people who must deal with overworked muscles. But it may also lead to helping people detect pain better. Foremost on the list would be diabetics who, due to neural damage, can't feel pain from ischemic muscles until it's too late.
A special kind of pain
In classic experiments, researchers elsewhere applied tourniquets to volunteers' arms, drastically cutting the flow of oxygen to the muscles. But the volunteers felt no pain until they exercised their arms.
Clearly, say Elde and his colleagues, the neurons that sense oxygen deprivation weren't responding to low oxygen levels directly. Instead, they must have been responding to chemicals released into (or depleted from) the fluid that bathed the working, oxygen-starved muscle cells. But if not lactic acid, what?
In a series of experiments, the Minnesota and Oregon researchers found that it is lactic acid, but it has a helper—a small molecule called ATP, which is also released by ischemic muscle. Together, the two chemicals get the attention of pain nerves.
How it works:
• When a muscle cell is starved for oxygen, it leaks lactic acid into the surrounding fluid, causing a pH drop.
• ATP also leaks out. It diffuses through the fluid and attaches to a protein on the outer membranes of the pain neurons. As a result, the protein changes shape; this evokes a response in a neighboring protein.
• The neighboring protein is an acid detector, and its response is to increase its sensitivity. Now the neuron can sense the pH drop and pass the signal up to the brain.
This multistep mechanism likely allows the body to distinguish oxygen starvation from other conditions that cause bodily fluids to become acidic, the researchers say.
Old neurons, new tricks?
Putting the finding to use for patients with diabetes, for example, would take a long time, but Elde is already thinking along those lines.
"In diabetic neuropathy, one of the first things to go is pain detection," he notes. "What if you could tease a neuron to restore health in [those patients]?" One way, he muses, might be to teach old neurons a new trick.
"For example, what if we could install these mechanisms in other types of neurons? Say, ones that sense vibration—those are resilient to neuropathy—and make them surrogate [pain detectors]?" he says. "We could entice surviving neurons to add pain reception to their repertoire."
The work is published in the journal Neuron.