Two molecules involved in perpetuating chronic pain have been identified by researchers at The Johns Hopkins University and the University of Maryland.

Opening the way to potential advances in pain treatment, the molecules also look to have a role in causing uninjured areas of the body to be more sensitive to pain when a nearby area has been hurt.

Shown above, mouse skin nerves actively responding to painful stimulus have been genetically engineered to glow green, while hairs are in yellow.

“With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain," says Xinzhong Dong, Ph.D., of Johns Hopkins. “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."

Chronic Pain and the Trigeminal Nerve

Chronic pain, which goes on for weeks, months or even years after an underlying injury or condition is resolved affects an estimated 20 to 25 percent of the population worldwide. The cause can be anything from nerve injuries and osteoarthritis to stress or cancer.

The researchers were looking a system of pain-sensing nerves in the faces of mice, known as the trigeminal nerve. The trigeminal nerve is a hefty bundle of tens of thousands of nerve cells.

Each cell is like 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 one of these bundles has individual pain sensing wires which split apart to cover a particular region of the face.

Signals are sent through the individual wires to the hubs of the cells and then travel to the spinal cord through a separate set of bundles. From the spinal cord, the signals are relayed to the brain, which interprets them as pain.

Why Pain Spreads

Researchers pinched the V2 branch of the trigeminal nerve for an extended time, and found that the V2 and V3 territories were extra sensitive to additional pain.

The spreading of pain to uninjured areas is common in those with chronic pain. Also it can be experienced in acute injuries. For example, when your thumb is hit with a hammer and your whole hand throbs with pain.

To determine why, the researchers studied pain-sensing nerves in the skin of mouse ears.

The trigeminal V3’s tinier branches extend into the skin of the lower ear. However, an entirely different set of nerves is responsible for the skin of the upper ear. The difference enabled the researchers to compare the responses of two unrelated groups of nerves that are close to each other.

To surmount the difficulty of monitoring nerve responses, Dong’s team placed a gene into the DNA of mice which made the primary sensory nerve cells glow green when activated. The pain-sensing nerves of the face are a subset of these.

Hypersensitivity in Injured and Uninjured Nerve Terminals

Next, patches of skin were bathed in capsaicin. Capsaicin is the active ingredient in hot peppers.

The result was the pain-sensing nerves lit up in both regions of the ear. But V3 nerves in the lower ear were much brighter than those of the upper ear.

The researchers’ conclusion was that pinching the connected though separate V2 branch of the trigeminal nerve had in some way sensitized the V3 nerves to “overreact” to the same amount of stimulus. You can see this in the video clip above.

Applying capsaicin to different areas resulted in more nerve branches coming from a pinched V2 nerve lighting up than those coming from an uninjured one.

This suggests that adding to the pain signals being sent to the brain, nerves that don’t normally respond to pain are able to modify themselves during prolonged injury.

Says Dong: “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.”

Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain Yu Shin Kim, Yuxia Chu, Liang Han, Man Li, Zhe Li, Pamela Colleen LaVinka, Shuohao Sun, Zongxiang Tang, Kyoungsook Park, Michael J. Caterina, Ke Ren, Ronald Dubner, Feng Wei, Xinzhong Dong Neuron, 23 January 2014 10.1016/j.neuron.2013.12.011

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