Pain, the saying goes, is your body telling you that something is wrong. What, then, is your body saying when you feel chronic, unending pain? Having conducted a recent investigation to answer this question, a team of researchers reports they have pinpointed two molecules, TRPVI and serotonin, involved in perpetuating chronic pain. These same two molecules also appear to perform a role in the phenomenon that causes uninjured parts of the body to be more sensitive when an area nearby has been hurt. "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," said Dr. Xinzhong Dong, associate professor of neuroscience at the Johns Hopkins University School of Medicine, in a press release. "With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain.”

Experiments in Pain

According to those who suffer, there’s pain and then there’s chronic pain. Caused by anything from nerve injury and stress to osteoarthritis and cancer, chronic pain can persist for weeks, months, or even years after an underlying condition is resolved. Such pain afflicts an estimated 20 to 25 percent of the population worldwide and about 116 million people in the U.S. Sufferers often find their pain is incurable and turn to treatments, medicinal as well as alternative, but these only sometimes help.

To better understand pain, Dong and his team of scientists focused on a system of nerves within the face, known collectively as the trigeminal nerve. The trigeminal nerve is a large bundle of tens of thousands of nerve cells, where each cell actually forms a long wire with a hub at its center. Altogether, the smaller hubs form a larger hub. On one side of this larger hub, three smaller bundles of wires — known as V1, V2, and V3 — branch off. Sensation signals travel through all these wires and hubs to the spinal cord and from there, the signals are relayed to the brain, which interprets them as pain.

The team explored the trigeminal nerve by conducting their research on mice. Having studied pain-sensing nerves in mouse ears, they understood that the smaller networks of the trigeminal V3 branch into the skin of the lower ear while an entirely different set of nerves branch into the skin of the upper ear. This distinction allowed the researchers to compare the responses of two unrelated groups of nerves that are in close proximity to each other. In particular, they wanted to see how pain could be spread to uninjured areas — typical in cases of chronic pain yet also experienced during acute injuries, as when a thumb is hit with a hammer and the whole hand throbs. Finally, as a way to monitor each mouse’s nerve responses, Dong’s team inserted a gene into the DNA of all the mice so that the primary sensory nerve cells would glow green when activated.

The experiment began: When the team of researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they discovered that the V2 and V3 territories were extra sensitive to additional pain. Next, when skin patches 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 connected-but-separate V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus. Applying capsaicin again to different areas, the researchers discovered that more nerve branches coming from a pinched V2 nerve lit up in comparison to those coming from an uninjured one.

The experiment suggested to the researchers that those nerves which normally don’t respond to pain may modify themselves during prolonged injury, adding to the pain signals being sent to the brain. The team decided to further explore the phenomenon with the help of their colleagues at the University of Maryland. They decided to explore TRPV1, a molecular sensor that helps to detect and regulate body temperature while also providing the sensation of scalding heat and pain.

Knowing that TRPV1 is needed to activate pain-sensing nerve cells, the researchers investigated its activity in the trigeminal nerve and discovered it was hyperactive in injured V2 nerve branches and in uninjured V3 branches, as well as in the branches that extended beyond the hub of the trigeminal nerve cell and into the spinal cord. Understanding that serotonin is involved in chronic pain, the researchers decided to explore the role it played in a TRPV1 activation study. A team, led by Dr. Feng Wei, blocked the production of serotonin, which is released from the brain stem into the spinal cord, and found that TRPV1 hyperactivity nearly disappeared.

“Chronic pain seems to cause serotonin to be released by the brain into the spinal cord,” Dong stated. “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.”

Source: Dong X, Kim YS, Han L, Li Z, LaVinka P, et al. Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain. Neuron. 2014.