Serotonin May Perpetuate Chronic Pain

Serotonin May Perpetuate Chronic Pain

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.”

Nerves in mouse skin  responding to painful stimulus have been genetically engineered to glow green. Hairs appear in yellow. Image courtesy of Johns Hopkins Medicine.

Nerves in mouse skin responding to painful stimulus have been genetically engineered to glow green. Hairs appear in yellow. Image courtesy of Johns Hopkins Medicine.

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.

Authored by: Pat Anson, Editor

There are 8 comments for this article
  1. anne groenewege at 4:06 pm

    Hello,
    I have just read this article on SSRI’s..I had an Empyema gallbladder 18 months ago, I was lucky to survive all the complications that it presented and especially the emergency situation it posed for the surgeons that did my operation to remove the gallbladder. I had post operative periotinitis, and a large fossa haematoma, ascites and a list of complications..The most terrible thing to come from all of this is the dysfunctional chronic abdominal pain and also in my groin and thigh..Doctors cannot explain the pain down into my groin and thigh but i am convinced that there has been extensive nerve and tissue damage during the op..The pain is terrible..I am on painkillers and have recently had T7-T10 nerve blocks that were unsuccessful..I told the pain specialist I believe the T11-T12 neves are the culprits, the cutaneous and also rectus abdominal sheath nerves muscles etc..the pain has not changed in 18 months..it is affected by everything to do with movement and bowel movements, digestion, i can’t lie flat on either my front or back without being in a lot of pain..I can’t stretch, bend, lift etc etc without it hurting..I am at the end of my tether..I take Mirtazapine for depression, valium for anxiety..i hate all of these drugs..I am a vibrant 56 yr old grandmother..or was..and am sick of the merry go round with doctors unable to help my pain..Serotonin how can that possibly be having any affect on my pain..it is damaged tissue and nerves that i bet are irrepairable..doctors just won’t do all they possibly can to get to the bottom of my pain..they should as they are doctors and they are the only people in the world that can have the skills to help people be free of pain..pills are not the answer..angry at choices doctors made when i first became ill with my gallbladder..they should have removed it before it became so dangerous..fed up..crying out for help..where do you go in the end..serotonin has nothing to do with it..please…

  2. Don at 4:40 pm

    Not surprising at all, for a few increasing serotonin does not make for a happy person, apart from increasing pain it turns a persons personality a 180 degrees, from being mild mannered to outbursts of rage and anger.

  3. Nina at 7:24 pm

    So is there an antidepressant that would be better than others at fighting depression (because if you are in pain chances are good that you are depressed) but not increasing?

  4. annie at 10:00 pm

    This makes sense. My daughter and I both have CRPS. She was recently diagnosed as bipolar and ever since she has started serotonin enhancing meds……her pain is worse and she has more flares.

  5. Mark at 7:28 pm

    The popular notion, marketed heavily by the medical industry, of serotonin as the happy substance is but a myth. Several research studies found the chemical increases free radical production, inflammation, brain dysfunction, and many other pathologies (google/bing “Tryptophan Side Effects: L-Tryptophan Is Far From Harmless”). These findings would readily support and re-affirm serotonin’s involvement in chronic pain as found in this new study.

  6. Anonymous at 11:41 am

    Interesting! What is particularly disturbing is that virtually all women who present with pain are assumed to be depressed and given SSRIs! I wonder if this has an effect on amplifying the pain?

  7. Dru at 9:35 am

    Am not surprised by these findings! Have tried to make dictors understand for years that the pain is out of proportion to the trauma or injury! How many millions has it taken for this “research” to take place? And how many years will it take to get local doctors to comprehend the impact of this on “chronic pain?”