“Some people have an injury or a surgery, and they go on to be pain free for the rest of their lives. Other people develop chronic pain. Why is that?” says Dr. Bradley Taylor of the University of Pittsburgh School of Medicine.
That question has been a central focus of his 30+ year career.
Chronic pain, which affects 50 million Americans, was once assumed to be a case of healing gone wrong. In a seminal 2013 paper in Science, Taylor’s lab helped establish that another major reason pain can persist is because something’s amiss in an altogether different process—the body’s own innate ability to quell pain, known as endogenous analgesia.
In the more immediate aftermath of an injury or surgery, it smarts for a while, and for good reason—this “hypersensitivity,” in pain-researcher parlance, keeps you protecting yourself while you heal. But at a certain point, a body really has to get on with the business of living, and biology cuts you a break. In his studies of endogenous analgesia, Taylor went on to show that a particular group of cells with receptors for a neurotransmitter called neuropeptide Y—cells dubbed Y1R neurons—are key to the phenomenon.
And in a new paper published in Nature, the professor of anesthesiology and perioperative medicine and his collaborators have uncovered fascinating new wrinkles in the endogenous-analgesia story.
Seven years ago, Taylor met Dr. J. Nicholas Betley, a researcher at the University of Pennsylvania who had observed something curious in the lab. When an animal was hungry, behavioral signs of acute pain subsided, and in fact, the effects were even more powerful than ibuprofen. And he wondered: Was this endogenous analgesia summoned out of necessity, so the brain could prioritize the most imminent threat of the moment? Taylor was intrigued, and a fruitful collaboration was born.
In a mouse model, the Pitt/Penn team discovered that, within a region of the brainstem known as the parabrachial nucleus, Y1R neurons were scattered throughout and were activated by not only hunger but also thirst and fear—introduced with the scent of a fox—as well as the chronic pain signals Taylor had found in his earlier studies.
Further, within a separate brain region called the arcuate nucleus of the hypothalamus, which is known to be activated by hunger, the neurons of that circuitry released neuropeptides that acted on Y1R neurons in the parabrachial nucleus.
And here it was: A natural on/off switch for chronic pain that enables a mouse to prioritize what’s important and save its tail.
Advanced imaging at Penn showed this phenomenon in action at the cellular level, in real time. And in Taylor’s behavioral studies in a mouse model of neuropathic pain associated with nerve injury, the mice stopped responding with hypersensitivity to mild stimulus (a light touch or a drop of harmless, cold liquid on the skin). A third collaborator, Dr. Ann Kennedy at Scripps Research Institute, further illustrated the findings of the study with computational models of how the brain chooses between pain and survival needs.
“We knew this particular brain region, the parabrachial nucleus, was important to chronic pain before. Now we have found the specific cells scattered throughout it that form an important hub where many competing needs converge, and chronic pain is modulated,” said Taylor.
The findings point to promising new avenues for future studies to explore: Could the activity of Y1R neurons serve as chronic-pain biomarker? And could this “hub” within the mouse brain eventually translate to an on/off switch for chronic pain in patients, and a target for drug development? Answering these questions will take decades more in this story already decades in the making, but Taylor is excited for the long haul.
“If we can better understand how we control our own pain,” said Taylor, “perhaps we can mimic that control with new treatments.”
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