Seratonin, a neurotransmitter long thought to promote feelings of well-bring and happiness, could also cause chronic pain by making nerves hyperactive, according to a new study at Johns Hopkins University and the University of Maryland.
The discovery could help scientists understand and develop new ways of treating Complex Regional Pain Syndrome (CRPS), trigeminal neuralgia, and other chronic pain conditions.
In studies on mice, researchers identified two molecules that appear to have a role in the phenomenon that causes uninjured parts of the body to become sensitive to pain when an area nearby has been hurt. A summary of their research is published in the journal Neuron.
“With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain,” says Xinzhong Dong, PhD, an associate professor of neuroscience at the Johns Hopkins University School of Medicine
“We found that persistent pain doesn’t always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it.”
In their research, the scientists focused on a system of pain-sensing nerves within the faces of mice, known as the trigeminal nerve. The trigeminal nerve is a bundle of tens of thousands of nerve cells. Each cell is a long “wire” with a hub at its center; the hubs are grouped together into a larger hub.
On one side of this hub, three smaller bundles of wires — V1, V2 and V3 — branch off. Each bundle contains individual pain-sensing wires that split off to cover a specific area of the face. Signals are sent through the wires, and travel through the spinal cord to the brain, which interprets them as pain.
When the researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they found that the uninjured V2 and V3 territories also became sensitive to pain.
To figure out why, Dong’s team inserted a gene into the DNA of mice so that the primary sensory nerve cells in their ears would glow green when activated.
A video of nerve cells in a mouse ear “lighting up” in response to pain can be seen here.
When the skin of their ears were bathed in a dose of capsaicin — the active ingredient in hot peppers — the pain-sensing nerves lit up in both regions of the ear. But the V3 nerves in the lower ear were much brighter than those of the upper ear. The researchers concluded that pinching the V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus.
This suggests that nerves that don’t normally respond to pain can modify themselves during prolonged injury, adding to the pain signals being sent to the brain.
Knowing from previous studies that the protein TRPV1 is needed to activate pain-sensing nerve cells, the researchers next looked at its activity in the trigeminal nerve. They showed it was hyperactive in both injured V2 nerve branches and in the uninjured V3 branches, as well as in the branches that extend into the spinal cord.
Researchers also found that when they blocked the production of serotonin, which is released from the brain stem into the spinal cord, the hyperactivity of TRPV1 nearly disappeared.
“Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some non-pain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain,” explained Dong.
The study was supported by grants from the National Institute of Dental and Craniofacial Research, the National Institute of General Medical Sciences, the National Institute of Neurological Disorders and Stroke, the Johns Hopkins University Brain Science Institute and Howard Hughes Medical Institute.