Editors' ChoiceNeuroscience

Feeling No Pain

Sci. Signal.  01 Jul 2014:
Vol. 7, Issue 332, pp. ec183
DOI: 10.1126/scisignal.2005644

Infection by Mycobacterium ulcerans causes Buruli ulcers, which begin as painless subcutaneous nodules and progress to necrotic open wounds. M. ulcerans secrete the toxin mycolactone, which is essential for host colonization. Angiotensin II is a peptide hormone in animals that binds to two types of receptors. Type I receptors (AT1Rs) play a pivotal role in homeostasis of the cardiovascular system, whereas type II receptors (AT2Rs) are less well characterized and may play a role in pain perception (see Danser and Anand). Marion et al. found that in M. ulcerans–infected mice, mycolactone binds to and activates AT2Rs to reduce pain. Mice injected with M. ulcerans or with mycolactone had reduced responses to pain but no nerve damage. Exposing cultured cells to mycolactone led to slow and reversible hyperpolarization that was blocked by genetic or pharmacological inhibition of AT2R. Mycolactone-mediated hyperpolarization was sensitive to general K+ channel inhibitors and to knockdown of the K2P family channel TRAAK. Activation of AT2R activates phospholipase A2 to promote release of arachidonic acid, which is converted by cyclooxygenases into prostaglandin H2, which is further metabolized to other prostaglandins, such as prostaglandin E2. Inhibition of phospholipase A2, cyclooxygenases, or prostaglandin E synthase 2 blocked hyperpolarization of cells exposed to mycolactone, whereas application of prostaglandin E2 increased TRAAK-mediated release of K+. In AT2R-knockout mice or mice with pharmacological inhibition of AT2R or cyclooxygenase-1, infection with M. ulcerans did not inhibit pain perception, and infection of AT2R-knockout mice did not produce ulcers. Thus, AT2R likely plays a key role in the painless progression of Buruli ulcers by promoting the production of inflammatory mediators that also reduce nerve activity and thus pain in the infected tissue.

E. Marion, O.-R. Song, T. Christophe, J. Babonneau, D. Fenistein, J. Eyer, F. Letournel, D. Henrion, N. Clere, V. Paille, N. C. Guérineau, J.-P. Saint André, P. Gersbach, K.-H. Altmann, T. P. Stinear, Y. Comoglio, G. Sandoz, L. Preisser, Y. Delneste, E. Yeramian, L. Marsollier, P. Brodin, Mycobacterial toxin induces analgesia in Buruli ulcer by targeting angiotensin pathways. Cell 157, 1565–1576 (2014). [PubMed]

A. H. J. Danser, P. Anand, The angiotensin type II receptor for pain control. Cell 157, 1504–1506 (2014). [PubMed]

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