Victor Meseguer 1 , Yeranddy A. Alpizar 2 , Enoch Luis 1 , Sendoa Tajada 3 , Bristol Denlinger 1 , Otto Fajardo 1 , Jan-Albert Manenschijn 1 , Carlos Fernández-Peña 1 , Arturo Talavera 2 , 4 , Tatiana Kichko 5 , Belén Navia 6 , Alicia Sánchez 2 , Rosa Señarís 6 , Peter Reeh 5 , María Teresa Pérez-García 3 , José Ramón López-López 3 , Thomas Voets 2 , Carlos Belmonte 1 , Karel Talavera 1 , 2 , 7 , Félix Viana a , 1 , 7
20 January 2014
Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.