Mast cells in nerve pain

Mast cells are heavily involved in the generation and sensation of pain. The role of mast cells in neurogenic pain (also called nerve pain or neuropathy) is well established and is responsible for a number of painful conditions.

Pain is transmitted like this:

  1. You first feel the pain in nerve endings called nociceptors.
  2. These nerve endings and capillaries in the nearby tissue form a “pain unit” that sends pain signals.
  3. Mast cells are often found close to these nerve endings and capillaries. They release mediators like prostaglandins, histamine and bradykinin.
  4. Nociceptors release mediators like substance P, VIP and CRH, which activate mast cells.
  5. Mast cells then release mediators that increase permeability of the vessels and sensitize the nociceptors. This cycle, in which the nerve endings activate mast cells and the mast cells activate the nerve endings, is called a positive feed back loop. The end result is neurogenic inflammation, or inflammation caused by nerves.

Mast cells can communicate with nerve endings in a number of ways. The first way is by releasing mediators, which may bind to receptors on the nerve cells. A second way is by mast cells sticking to nerve cells through molecules like CADM-1 and N-cadherin; they are able to send signals when their membranes are touching. A third way is by the nerve cells ingesting mediators released by mast cells. These mediators are then transported to other nerve cells, where it can affect which genes are turned on and used.

Mast cells also draw other immune cells to the site of inflammation, like neutrophils and T cells. These cells also release mediators that increase pain, forming another positive feedback loop. The result is that inflammation can spread beyond the initial site of pain, causing a secondary, larger pain response. Hyperalgesia is an exaggerated pain response that is more severe than expected based upon the injury. Mast cells are thought to be directly involved in hyperalgesia and histamine is thought to cause this heightened pain sensation.

Chronic pain has been associated with mast cell degranulation. Degranulation close to colonic nerves is correlated with abdominal pain in IBS patients. Tryptase and histamine can also activate enteric nerves, causing the nerves to be oversensitive. Esophageal pain is also a function of mast cell degranulation.

The specific mechanism of bladder pain due to interstitial cystitis is not clear. However, mast cells are often elevated in IC patients, and contribute to inflammation. It is thought that activation of bladder nerves causes release of substance P by local nerve endings, which activates mast cells.

Overly sensitive and painful skin is sometimes a function of mast cells as well. A significant increase in mast cells has been found in the dermis of fibromyalgia patients. Chronic granulomatous inflammation of the skin causing pain has also been found to be from degranulation of mast cells.



Heron, Anne, Dubayle, David. 2013. A focus on mast cells and pain. Journal of Neuroimmunology 264 (2013) 1–7.

Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., 2001. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944.

Theoharides, T.C., Kempuraj, D., Sant, G.R., 2001. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57, 47–55.

Theoharides, T.C., Donelan, J., Kandere-Grzybowska, K., Konstantinidou, A., 2005. The role of mast cells in migraine pathophysiology. Brain Res. Brain Res. Rev. 49, 65–76.

Gao, G., Ouyang, A., Kaufman, M.P., Yu, S., 2011. ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Dis. Esophagus 24, 194–203.

4 Responses

  1. Yvonne April 23, 2015 / 12:50 pm

    Thanks so very much for this. My Mom was on morphine post transplant but felt way more pain than there was. I would only touch her and she would be vocalize pain response. I never understood why until now. Thanks so very much

  2. Yvonne April 23, 2015 / 12:51 pm

    Why do doctors not know this?

  3. Michelle Curry April 13, 2016 / 5:16 pm

    Thanks for posting this article. People think I’m crazy when I say “My skin hurts. I can’t explain it, but don’t touch me.”

    Is there anything we mast cell patients can do to relieve this skin pain? It hurts to even have clothes on, or just sit and be still. Sometimes it lasts for 3-5 days at a time. I’m so sensitive to touch.

    I’m on all the H1 and H2’s, hydroxyzine, doxepin, singulair, klonopin…….. apparently none of these help with my painful skin issues. Any advice is much appreciated.

    • Lisa Klimas April 13, 2016 / 9:22 pm

      The burning skin for me is helped a lot by taking aspirin or ketorolac. I found that alpha lipoic acid also helped this a bit for me, but I had to stop taking it because it just blew up my already complicated med schedule. Planning to try again at some point. Cromolyn cream also helps with the burning, although it’s more superficial relief. Now that I’m thinking about it, blocking TNF might help here and I take a TNF blocker (Enbrel, for rheumatoid arthritis) but ketotifen also can decrease TNF production after 4-5 months.

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