By David Dobbs
Chronic pain is both one of the world’s most costly medical problems, affecting one in every five people, and one of the most mysterious. In the past two decades, however, discoveries about the crucial role played by glia — a set of nervous system cells once thought to be mere supports for neurons — have rewritten chronic pain science.
These findings have given patients and doctors a hard-science explanation that chronic pain previously lacked. By doing so, this emerging science of chronic pain is beginning to influence care — not by creating new treatments, but by legitimizing chronic pain so that doctors take it more seriously.
Although glia are scattered throughout the nervous system and take up almost half its space, they long received far less scientific attention than neurons, which do the majority of signaling in the brain and body. Some types of glia resemble neurons, with roughly starfish-like bodies, while others look like structures built with Erector sets, their long, straight structural parts joined at nodes.
When first discovered in the mid-1800s, glia — from the Greek word for glue — were thought to be just connective tissue holding neurons together. Later they were rebranded as the nervous system’s janitorial staff, as they were found to feed neurons, clean up their waste and take out their dead. In the 1990s they were likened to secretarial staff when it was discovered they also help neurons communicate. Research over the past 20 years, however, has shown that glia don’t just support and respond to neuronal activity like pain signals — they often direct it, with enormous consequences for chronic pain.
If you’re hearing this for the first time and you’re one of the billion-plus people on Earth who suffer from chronic pain (meaning pain lasting beyond three to six months that has no apparent cause or has become independent of the injury or illness that caused it), you might be tempted to say that your glia are botching their pain-management job.
And you’d be right. For in chronic pain, researchers now believe, glia drive a healthy pain network into a dysregulated state, sending false and destructive pain signals that never end. Pain then becomes not a warning of harm, but a source of it; not a symptom, but, as Stanford pain researcher Elliot Krause puts it, “its own disease.”
How the pain system works — and goes awry.
The pain system generally works in three distinct stages.
First, when an injury or ailment causes damage — let’s say you just touched a hot pan — long nerve fibers in your finger sense the damage and shoot a pain message toward your brain. In the second stage, those signals enter your spinal column and, in a handoff monitored and sometimes tweaked by nearby glia, jump to other neurons within the spinal cord. Finally, in this alarm system’s third stage, those spinal cord neurons carry the signals to a spot in your cerebral cortex related to your fingertip and create the sensation of burning pain. You curse.
The first part of this alarm system — carrying the pain signal toward the central nervous system — runs largely on a highly efficient autopilot. Its main players are the long pain-sensitive neurons that run from finger to spinal cord and quickly trigger a reflex that makes you jerk back your hand.
In stage two, when these signals approach the brain and spinal cord, however, things get tangly. It is here, at the handoff from peripheral to central nervous system, that a profusion of glia heavily regulate pain signals by, say, amplifying or decreasing their intensity or duration. And it’s here that things can go amiss and trigger chronic pain. As a flood of recent research has shown, chronic pain develops because the glia accelerate the pain system into an endless inflammatory loop that provokes the nerves into generating a perpetual pain alarm.
It’s still not clear exactly how or why this glial mismanagement develops. It can emerge either after an injury or seemingly out of nowhere. Pain from one or even multiple injuries, as in a car wreck, ordinarily lasts days or weeks and then tapers off to nothing. But sometimes the glia’s regulatory system continues the pain signals after the tissue heals. These may even spread to other areas, causing yet more pain.
Glia can create a tough mess to untangle.
In theory, identifying glia as chronic pain’s culprits should make it easier to find a solution. Unfortunately it hasn’t, at least not yet. You can’t just knock glia out — they’re too important — and current painkillers don’t help because they target neurons, not glia.
And glia are ludicrously versatile. They transmit information through dozens of communication pathways. “Pretty much every way that neurons communicate,” said Doug Fields, a glia researcher with the National Institutes of Health, “glia also use.” In a kinder world, these pathways would offer targets for drugs or other treatments. But in the dauntingly complex systems in which glia operate, those targets have so far proved fruitless. No treatment has yet made it from bench to bedside.
This shouldn’t surprise us, said Dr. Fields: “Neuroscientists have studied neurons for over a century, but they are playing catch-up with glia.”
David Clark, a Stanford pain researcher and clinician at the Palo Alto Veteran’s Affairs hospital, suspected that part of the problem lies in the pain system’s built-in redundancy. Glia seem to have so many ways to transmit pain signals that even if a treatment blocks one, they promptly find another. Dr. Clark believes that outwitting this vast system of glial regulation may require novel strategies.
“This is not going to offer up a target you can just hit with a drug or a genetic switch. It may require something wholly new, like figuring out how to turn off an entire family of genes at some crucial spot,” said Dr. Clark.
Your pain has a source.
The realization over the past 20 years that glia underlie chronic pain does offer two substantial sources of comfort.
For one, scientists now at least have some idea where to seek a solution — the glia. They haven’t yet found easily detectable biomarkers that could demonstrate in a live person that glia (or other elements) are causing chronic pain. But the underlying science is robust and steadily growing more so.
For pain sufferers, this is a welcome validation of their reality. “Learning this,” said Cindy Steinberg, the national director of policy and advocacy at the U.S. Pain Foundation, and a chronic pain patient herself, “is enormously helpful to those of us who suffer chronic pain.” In a chronic-pain support group Ms. Steinberg runs, she said that people find it a huge affirmation to learn there’s a distinct biology underlying their pain. It confirms what they’ve long known but often see doubted by doctors and friends: That their pain is as real as any other.
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