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Cited by 253Ion Channels and ReceptorsThermoregulation and physiological responsesPain Mechanisms and Treatments

The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not

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Romanovsky, Andrej A., Almeida, Maria C., Garami, Andras, Steiner, Alexandre A., Norman, Mark H., Morrison, Shaun F., Nakamura, Kazuhiro, Burmeister, Jeffrey J. +1 more·2009·Pharmacological Reviews
DOI 10.1124/pr.109.001263PMC PMC2763780
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Abstract

The development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel as pain therapeutics has revealed that these compounds cause hyperthermia in humans. This undesirable on-target side effect has triggered a surge of interest in the role of TRPV1 in thermoregulation and revived the hypothesis that TRPV1 channels serve as thermosensors. We review literature data on the distribution of TRPV1 channels in the body and on thermoregulatory responses to TRPV1 agonists and antagonists. We propose that two principal populations of TRPV1-expressing cells have connections with efferent thermoeffector pathways: 1) first-order sensory (polymodal), glutamatergic dorsal-root (and possibly nodose) ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. We further hypothesize that all thermoregulatory responses to TRPV1 agonists and antagonists and thermoregulatory manifestations of TRPV1 desensitization stem from primary actions on these two neuronal populations. Agonists act primarily centrally on population 2; antagonists act primarily peripherally on population 1. We analyze what roles TRPV1 might play in thermoregulation and conclude that this channel does not serve as a thermosensor, at least not under physiological conditions. In the hypothalamus, TRPV1 channels are inactive at common brain temperatures. In the abdomen, TRPV1 channels are tonically activated, but not by temperature. However, tonic activation of visceral TRPV1 by nonthermal factors suppresses autonomic cold-defense effectors and, consequently, body temperature. Blockade of this activation by TRPV1 antagonists disinhibits thermoeffectors and causes hyperthermia. Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed.

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  1. The immediate effects of the first administration of CAP or RTX on Tb regulation (the subject of this section) are different from the delayed effects and from those after repeated administration of these drugs (section IV.C.). Upon the first administration per os, subcutaneously, intramuscularly, intraperitoneally, intravenously, intrathecally, intracerebroventricularly, or into the POA in a variety of species (i.e. mice, rats, guinea pigs, ground squirrels, rabbits, ferrets, goats, dogs, and cats), CAP and RTX cause hypothermia (for review, see Hori, 1984; Szallasi and Blumberg, 1999; Szolcsányi, 2004; Caterina, 2007; see also Table 2 and Figs. 2 and 3). Some species (rabbits and ground squirrels) are less sensitive than others (mice, rats, and cats) (Hori, 1984), and, according to most studies, the avian species are highly insensitive to the hypothermic action (and the nonthermoregulatory actions) of CAP (Mason and Maruniak, 1983; Pierau et al., 1986; Szolcsányi et al., 1986). The insensitivity of the avian TRPV1 channel to CAP allows birds to feed on hot peppers and disseminate pepper seeds (Jordt and Julius, 2002). It has been reported that ducks tolerate a cumulative intravenous dose of CAP as high as 1 g/kg without any apparent thermoregulatory changes or signs of distress (Geisthövel et al., 1986). However, a relatively low dose of CAP (10 mg/kg i.v.) has been shown to cause hypothermia in chickens (Mahmoud et al., 2007).
  2. Cabanac et al. (1976), Obál et al. (1979, 1980, 1982); Benedek et al. (1983); Szolcsányi (1983).
  3. In contrast to the impaired thermoregulation of desensitized animals, genetic ablation of TRPV1 does not cause gross changes in Tb regulation in response to either heat or cold challenges (Szelényi et al., 2004; Iida et al., 2005). There is, however, a report showing that Trpv1 KO mice can defend their deep Tb against severe environmental cooling better than their wild-type counterparts (Motter and Ahern, 2008), but such changes were not seen in a similar study by Iida et al. (2005). Considering that thermoregulatory experiments in mice have multiple pitfalls (Rudaya et al., 2005), more extensive studies of Tb regulation in Trpv1 KO mice may be warranted. It should be further noted that negative results obtained in KO animals are typically inconclusive, because various types of compensatory changes may restore the function of interest, even if the knocked out gene is normally the one responsible for this function. Several new strategies to silence the Trpv1 gene (namely, those involving antisense oligonucleotides, small interfering RNAs, or short hairpin RNAs) have recently been used in pain research (Christoph et al., 2006, 2007, 2008). It would be interesting to study the regulation of Tb in these new models, especially because compensation patterns in different models are likely to differ (Christoph et al., 2008).
  4. It seems clear that TRPV1 channels do not play the role of thermosensors for Tb regulation under normal conditions. However, it is not completely clear how to classify the nonthermal, tonic, inhibitory effect of visceral TRPV1 channels on autonomic cold-defense effectors under physiological conditions. According to the most recent review by Gavva (2008), this effect shows that the TRPV1 channel “regulates Tb,” but whether this conclusion is legitimate depends on the definition of thermoregulation. If by regulation we mean adjusting core Tb (the main control variable) based on its changes via negative feedback or based on changes in Tsk (the auxiliary variable) via negative or positive feedback, then TRPV1 channels are not involved in Tb regulation. They sense neither core Tb nor Tsk; hence, they are uninvolved in the control of the main variable via feedback mechanisms. Consequently, if one subscribes to a traditional, conservative definition of Tb regulation as a feedback control, a proper conclusion would be that TRPV1 channels are uninvolved in normal thermoregulation and instead tonically modulate Tb by modulating thermoeffector activity in response to nonthermal stimuli.
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Authors
Romanovsky, A. A., Almeida, M. C., Garami, A., Steiner, A. A., Norman, M. H., Morrison, S. F., Nakamura, K., Burmeister, J. J., & Nucci, T. B.
Affiliations
Oregon National Primate Research Center (US)
ORCID
Venue
Pharmacological Reviews
Publisher
Elsevier BV
Published
2009-09
Volume
61
Issue
3
Pages
228-261
ISSN
0031-6997 (ISSN-L)
DOI
10.1124/pr.109.001263
PMC
PMC2763780
OpenAlex
W2167044638
Cited by
253
References
324
Citations by year
2026: 5 · 2025: 12 · 2024: 9 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 16 · 2019: 10 · 2018: 15 · 2017: 18 · 2016: 19 · 2015: 23 · 2014: 22 · 2013: 19 · 2012: 15
FWCI
1.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacological Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS041233, R01NS40987, R01 NS 41233, R01NS040987)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Physiology › Thermoregulation and physiological responses
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords
TRPV1, thermoregulation, temperature sensors, TRPV1 antagonists, hyperthermia, dorsal root ganglion neurons, nodose ganglion, TRPV1 desensitization, pain therapeutics
MeSH terms
Animals, Body Temperature Regulation, Humans, Models, Biological, TRPV Cation Channels

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