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GABA blocks pathological but not acute TRPV1 pain signals

Official URL:https://doi.org/10.1016/j.cell.2015.01.022
PubMed:View item in PubMed
Creators Name:Hanack, C. and Moroni, M. and Lima, W.C. and Wende, H. and Kirchner, M. and Adelfinger, L. and Schrenk-Siemens, K. and Tappe-Theodor, A. and Wetzel, C. and Kuich, P.H. and Gassmann, M. and Roggenkamp, D. and Bettler, B. and Lewin, G.R. and Selbach, M. and Siemens, J.
Journal Title:Cell
Journal Abbreviation:Cell
Volume:160
Number:4
Page Range:759-770
Date:12 February 2015
Keywords:Autocrine Communication, Cultured Cells, Feedback, GABA-B Receptors, Inbred C57BL Mice, Neurons, Pain, TRPV Cation Channels, Transgenic Mice, gamma-Aminobutyric Acid, Animals, Mice
Abstract:Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.
ISSN:0092-8674
Publisher:Cell Press / Elsevier (U.S.A.)
Item Type:Article

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