In Hot Pursuit of the Elusive Heat Transducers

How Many Different Somatosensory Heat Transducers Are There? Considering the two recent studies of mice that do not express VR1, and previous in vivo and in vitro observations, one can postulate that there are at least three somatosensory heat transducers that sense distinct bands of the temperature spectrum.(1) Extreme heat. As discussed above, the recent evidence from knockout mice suggests that, in intact animals, temperatures of about 50°C and above are encoded by the combined action of VR1 and some non-VR1 mechanism.(2) Noxious heat. The demonstration that VR1 does not contribute to behavioral responses evoked by temperatures below 50°C leaves no identified molecule as a strong candidate to transduce the lower range of noxious temperatures to which animals respond. The other three known members of the vanilloid receptor family, VRL-1, SIC, and VR.5′sv, are also expressed in small-diameter sensory neurons but are not activated in vitro by temperatures of at least 52°C, 47°C, and 50°C, respectively. Thus, it would seem that no known member of the vanilloid receptor family can account for the detection of noxious heat from pain threshold up to ∼50°C. Dorsal root ganglion neurons in vitro do express lower-threshold heat-evoked currents that might transduce this range of temperatures in vivo, but the underlying ion channels have not yet been identified.(3) Warmth. There is an inherent interest in understanding and treating pain, and most attention in the search for heat transducers has focused on mechanisms for detection of noxious temperatures. However, the commonplace sensation of nonnoxious warmth is essential to the survival of the organism, allowing precise regulation of body temperature. Although a variety of heat-activated currents have been described in dorsal root ganglion neurons, none seems suited to mediate warmth sensation, with the possible exception of a nonselective ion channel that is activated by temperatures from 25°C to 49°C in vitro (Reichling and Levine 1997xReichling, D.B and Levine, J.D. Proc. Natl. Acad. Sci. USA. 1997; 94: 7006–7011Crossref | PubMed | Scopus (83)See all ReferencesReichling and Levine 1997).In addition to sensing external temperatures at the body surface, temperature regulation depends on internal thermoreception. A large body of work has shown that in regions of the hypothalamus critical for temperature regulation, warmth-sensitive neurons express nonselective ion channels activated by temperatures just above body temperature (Hori et al. 1999xHori, A, Minato, K, and Kobayashi, S. Neurosci. Lett. 1999; 275: 93–96Crossref | PubMed | Scopus (32)See all ReferencesHori et al. 1999). Is There a Functional Identity for the Vanilloid Receptor Family? An intriguing issue that surrounds the work discussed in this review is: does the vanilloid receptor family as a whole have a distinct functional identity? The original identification of VR1 based on its activation by capsaicin gave rise to the operational designation “vanilloid receptors.” However, sensitivity to this and other exogenous substances may have little relevance to the endogenous functions of these molecules. Possible endogenous specific agonists, in addition to protons (Caterina et al. 1997xCaterina, M.J, Schumacher, M.A, Tominaga, M, Rosen, T.A, Levine, J.D, and Julius, D. Nature. 1997; 389: 816–824Crossref | PubMed | Scopus (4860)See all ReferencesCaterina et al. 1997), are now beginning to be evaluated, including the cannabinoid anandamide (Zygmunt et al. 1999xZygmunt, P.M, Petersson, J, Andersson, D.A, Chuang, H, Sorgard, M, Di Marzo, V, Julius, D, and Hogestatt, E.D. Nature. 1999; 400: 452–457Crossref | PubMed | Scopus (1478)See all ReferencesZygmunt et al. 1999) and the lipoxygenase product 12-(S)-hydroperoxyeicosatetraenoic acid (12-(S)-HPETE), which is much more effective than anandamide at activating VR1 (Hwang et al. 2000xHwang, S.W, Cho, H, Kwak, J, Lee, S.Y, Kang, C.J, Jung, J, Cho, S, Min, K.H, Suh, Y.G, Kim, D, and Oh, U. Proc. Natl. Acad. Sci. USA. 2000; 97: 6155–6160Crossref | PubMed | Scopus (796)See all ReferencesHwang et al. 2000). Whether vanilloid receptors other than VR1 are sensitive to these putative endogenous agonists remains to be determined. In the future, identification of potential endogenous ligands that act at physiological concentrations could be a key to refining the definition of the vanilloid receptor family in functional terms.Perhaps, as suggested specifically for VR1, these molecules constitute a family of sensory transducers that integrate multiple pain-producing stimuli (Tominaga et al. 1998xTominaga, M, Caterina, M.J, Malmberg, A.B, Rosen, T.A, Gilbert, H, Skinner, K, Raumann, B.E, Basbaum, A.I, and Julius, D. Neuron. 1998; 21: 531–543Abstract | Full Text | Full Text PDF | PubMed | Scopus (1950)See all ReferencesTominaga et al. 1998). This novel concept is in striking contrast to the very narrowly tuned selectivity that is a defining characteristic of transducers in other sensory systems. The concept, however, has intuitive appeal in the case of the vanilloid receptors since, unlike other receptor cells, nociceptive nerve fibers are themselves polymodal receptors that integrate multiple stimulus modalities. On the other hand, recent reports that the vanilloid receptors, including VR1, are very widely expressed in the nervous system and some other tissues (4xCaterina, M.J, Rosen, T.A, Tominaga, M, Brake, A.J, and Julius, D. Nature. 1999; 398: 436–441Crossref | PubMed | Scopus (883)See all References, 12xMezey, E, Toth, Z.E, Cortright, D.N, Arzubi, M.K, Krause, J.E, Elde, R, Guo, A, Blumberg, P.M, and Szallasi, A. Proc. Natl. Acad. Sci. USA. 2000; 97: 3655–3660Crossref | PubMedSee all References, 16xSchumacher, M.A, Moff, I, Sudanagunta, S.P, and Levine, J.D. J. Biol. Chem. 2000; 275: 2756–2762Crossref | PubMed | Scopus (107)See all References) complicate the view of the vanilloid receptors as being fundamentally sensory transducers for nociception.Could the primary function of vanilloid receptors be to participate in cellular responses to tissue damage—to respond to damage rather than to avoid it? This idea fits well with the most salient finding from both knockout studies, that VR1 mediates inflammatory heat hyperalgesia, itself a response to tissue damage. The prominent intracellular presence of vanilloid receptors would also seem to support the idea that their cellular effects are far more complicated than simply depolarizing the neuronal cytoplasmic membrane. As the burgeoning field of vanilloid receptor research continues to flourish and expand into areas divergent from sensory transduction, this fascinating class of receptors might come to be viewed primarily as triggers that initiate multifaceted cellular responses to tissue damage. In this guise, they might yield the greatest potential clinical insights.*To whom correspondence should be addressed (e-mail: reichli@itsa.ucsf.edu).