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.

The TREK‐1 channel is a temperature‐sensitive, osmosensitive and mechano‐gated K+ channel with a regulation by Gs and Gq coupled receptors. This paper demonstrates that TREK‐1 qualifies as one of the molecular sensors involved in pain perception. TREK‐1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin‐activated nonselective ion channel. Mice with a disrupted TREK‐1 gene are more sensitive to painful heat sensations near the threshold between anoxious warmth and painful heat. This phenotype is associated with the primary sensory neuron, as polymodal C‐fibers were found to be more sensitive to heat in single fiber experiments. Knockout animals are more sensitive to low threshold mechanical stimuli and display an increased thermal and mechanical hyperalgesia in conditions of inflammation. They display a largely decreased pain response induced by osmotic changes particularly in prostaglandin E2‐sensitized animals. TREK‐1 appears as an important ion channel for polymodal pain perception and as an attractive target for the development of new analgesics.

The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat‐ and cold‐sensitive excitatory transient receptor potential (TRP) channels. However, we show here that the mechano‐gated and highly temperature‐sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo‐TRP channels in sensory neurons. TRAAK and TREK‐1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK‐1 controls heat responses of both capsaicin‐sensitive and capsaicin‐insensitive sensory neurons. Together TREK‐1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol. There is a [Have you seen ...?][1] (May 2009) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2009.107