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PUBLIC RELEASE DATE:
19-Jun-2014

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Contact: Priscille Brodin
priscille.brodin@inserm.fr
33-320-871-184
INSERM (Institut national de la santé et de la recherche médicale)
www.twitter.com/inserm

Can injuries to the skin be painless?

This news release is available in French.

When the body receives an injury to the skin, a signal is sent to the brain, which generates a sensation of pain. Teams led by Priscille Brodin in Lille and Laurent Marsollier in Angers have studied lesions in patients with Buruli ulcer, a tropical disease. In an article published in the journal Cell, they show that, despite the extent and severity of these wounds, they are less painful than others that seem relatively minor (e.g. scratches, low-degree burns). They discovered an analgesic mechanism that limits the transmission of pain signals to the brain. An understanding of this mechanism may be useful in developing new drugs for pain relief.

Buruli ulcer (caused by infection with Mycobacterium ulcerans) is the third most prevalent mycobacterial disease, after tuberculosis and leprosy. This tropical disease, which mainly affects children, causes ulcerative cutaneous lesions. The destruction of skin tissue is caused by mycolactone, a toxin secreted by the bacterium. Despite their size, the lesions are not especially painful in the early stages of the disease, explaining why patients are slow to seek medical help. The researchers explored the mechanism that causes these lesions to be painless.

Until then, it had been thought that the lack of pain in the early stages of the disease was related to the destruction of nervous tissue. In the present study, the researchers show using infected mice that this hypothesis is not supported by nerve degeneration, which occurs only in the advanced stages of the disease. They also injected the toxin into mice to observe its effects on the animals' sensitivity. The researchers show 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," explains Laurent Marsollier, a research fellow at Inserm.

A state-of-the-art imaging technique was used to demonstrate that mycolactone interacts with a neuronal receptor (angiotensin receptor 2), causing leakage of potassium. The potassium efflux causes neuronal hyperpolarisation, limiting the transmission of nerve impulses—which carry the pain signal—at local level.

The researchers then blocked the expression of this neuronal receptor in mice infected with the bacterium. 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 Mycobacterium ulcerans bacterium employs a novel infection strategy by using the toxin it secretes to prevent the pain associated with the lesions it causes.

"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," says Priscille Brodin, Inserm Research Director and co-author of this study. Indeed, the molecule that can block the action of the receptor does not belong to the class of analgesics in current use, such as paracetamol or opiates such as morphine. Generally speaking, clinicians are hoping for new drugs to fight pain, since the existing drugs all have limitations of greater or lesser importance in the context of personalised medicine.

Finally, according to the researchers, the receptor identified may be a target of choice, since another study showed that blocking it led to the reduction of pain in patients with herpes infections.

###

Further information

Buruli Ulcer – WHO factsheet : http://www.who.int/mediacentre/factsheets/fs199/en/

WHO photos (associated environment and lesions of greater and lesser severity) : http://www.who.int/buruli/photos/en/

Sources

Mycobacterial Toxin Induces Analgesia in Buruli Ulcer by Targeting the Angiotensin Pathways
Estelle Marion1,2†, Ok-Ryul Song1,2,3†, Thierry Christophe2†, Jérémie Babonneau2,
Denis Fenistein2, Joël Eyer4, Frank Letournel4, Daniel Henrion5, Nicolas Clere6,
Vincent Paille5, Nathalie C. Guérineau5, Jean-Paul Saint André7, Philipp
Gersbach8, Karl-Heinz Altmann8, Timothy Stinear9, Yannick Comoglio10,
Guillaume Sandoz10, Laurence Preisser11, Yves Delneste11, Edouard Yeramian12£,
Laurent Marsollier1,2,11£*, Priscille Brodin2,3£*

1Inserm Avenir, ATOMYcA Team, Inserm U 892, CNRS U 6299, Angers University Hospital and University of Angers, 4 rue Larrey 49 933 Angers, France.
2Inserm Avenir, Institut Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-440 Korea.
3Inserm U1019, CNRS UMR8204, University of Lille Nord de France, Institut Pasteur Lille, Center for Infection and Immunity, 1, rue du Professeur Calmette, 59000 Lille, France.
4UPRES - EA 3143, Neurobiology and Transgenesis Laboratory,
5Inserm 1083, CNRS UMR6214, Laboratory of Integrated Neurovascular and Mitochondrial Biology, 6Inserm U1063, Oxidative Stress and Metabolic Diseases,
7Pathology Laboratory,
8ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland.
9Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia.
10Inserm Avenir, Laboratories of Excellence, Ion Channel Science and Therapeutics Nice, Institute of Biology Valrose, iBV, Inserm U1091, CNRS UMR7277, University of Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
11Team 7, Inserm U892, CNRS U6299, University and University Hospital, CRCNA (Cancer Research Center Nantes-Angers), 4 rue Larrey 49 933 Angers, France.
12Structural Bioinformatics Unit, Institut Pasteur, Paris, France.

£E.Y., L.M. and P.B. are co-senior authors
† Equal contribution

Cell, 19 June 2014 ; DOI: 10.1016/j.cell.2014.04.040

Investigator contacts

Priscille Brodin, Inserm Research Director
Joint Research Unit 1019, Center for Infection and Immunity of Lille (Inserm – CNRS – Institut Pasteur Lille – University of Lille Nord de France)
ERC Host-Pathogen Interactions
Tel.: +33 320 87 11 84
priscille.brodin@inserm.fr

Laurent Marsollier, Inserm Research Fellow
Inserm Unit 892 - Inserm Avenir "ATOMycA" Team (Inserm – CNRS – Angers University Hospital and University of Angers)
Tel.: +33 672 20 54 03
laurent.marsollier@inserm.fr

Press contact

Juliette Hardy
presse@inserm.fr



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