By: 15 August 2014
Can injuries to the skin be painless?

Teams at Inserm studying lesions in patients with an ulcerative tropical disease have discovered an analgesic mechanism that limits the transmission of pain signals to the brain.

In an article published in Cell, they have shown that, despite the extent and severity of Buruli ulcer wounds, they are less painful than other injuries that seem relatively minor, such as scratches and low-degree burns.

Buruli ulcer is the third most prevalent mycobacterial disease after tuberculosis and leprosy. The disease mainly affects children, and causes ulcerative cutaneous lesions. The destruction of skin tissue is caused by mycolactone, a toxin secreted by Mycobacterium ulcerans, the infective agent.

Despite their size, the lesions are not especially painful in the early stages of the disease, and patients are often slow to seek medical help. Until recently, it was thought that the lack of pain in the early stages of the disease was related to the destruction of nervous tissue. The Inserm study has shown, however, that nerve degeneration occurs only in the advanced stages of the disease and that the presence of the toxin can inhibit pain on its own, with no effect on the nerves.

The bacterium, or more specifically its toxin, mycolactone, can interact with neurons and prevent the transmission of nerve signals, explaining the painless nature of the lesions,” explained Laurent Marsollier, a research fellow at Inserm.

State-of-the-art imaging was used to demonstrate that mycolactone interacts with a neuronal receptor (angiotensin receptor 2), causing leakage of potassium. The potassium efflux leads to neuronal hyperpolarisation, limiting the transmission of nerve impulses at a local level.

The researchers blocked the expression of this neuronal receptor in mice infected with M. ulcerans. Blocking the receptor prevented it from interacting with the mycolactone toxin, which re-established the animals’ sensitivity to pain, thus providing in vivo confirmation of the mechanism identified.

“The discovery of this mechanism, which limits pain in the cutaneous lesions during the early stages of the disease, opens up new possibilities in the search for new drugs to prevent pain,” said Priscille Brodin, Inserm Research Director and co-author of the study.

Marion, E., Song, O.-R., Christophe, T., et al. (2014) Mycobacterial toxin induces analgesia in Buruli ulcer by targeting the angiotensin pathways. Cell 157(7), 1565–1576