A national proposition?

Detection of innocuous temperatures allows an organism to select an appropriate environmental climate, while the ability to recognize noxious temperature extremes warns of impending tissue damage. For temperatures considered cold, the menthol receptor TRPM8 is activated when temperatures drop below ~26°C, thus making it an intriguing candidate as the molecular mediator of cold perception. However, confirmation of this hypothesis in vivo has eluded researchers until recently. Three independent research groups have reported that mice lacking this single gene are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Background The ability of all species to detect ever-changing environmental temperatures is critical for homeostasis and survival. Recently, three research groups, led by Bautista, Colburn, and Dhaka, have reported that mice with a disruption in the gene encoding the cold and menthol receptor TRPM8 exhibit remarkable deficiencies in a range of cold responses [1-3]. These results suggest that TRPM8 is the predominant detector of cold temperatures in vivo, and serves a number of important roles in somatosensation, nociception, and analgesia. The last decade has yielded remarkable advances in our understanding of the molecular basis of thermosensation and pain (nociception), particularly with the cloning of a number of temperature-gated, excitatory ion channels of the Transient Receptor Potential (TRP) family. The founding member of this family, TRPV1, is a polymodal receptor that detects noxious heat (>43°C), acidity, and capsaicin, the 'hot' component in chili peppers [4]. Subsequently, other members of the TRPV subfamily were shown to be gated by heat and warmth, including TRPV2, TRPV3, and TRPV4 [5]. Mice lacking each of these channels (except for TRPV2) have been generated, and all show profound deficits in thermosensory behaviors consistent with their roles as molecular thermosensors. While heat directly gates many TRPV channels, cold temperatures have been reported to activate two additional TRP channels. TRPA1 was initially reported to be activated by noxious cold (<17°C), but these results have been controversial [6]. More recent studies have shown TRPA1 to Published: 17 August 2007 Molecular Pain 2007, 3:23 doi:10.1186/1744-8069-3-23 Received: 24 July 2007 Accepted: 17 August 2007 This article is available from: http://www.molecularpain.com/content/3/1/23 © 2007 Daniels and McKemy; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.