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.
- AEA, arachidonoylethanolamide
- BAT, brown adipose tissue
- BBB, blood-brain barrier
- BCTC, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide
- 1>CAP, capsaicin
- CPZ, capsazepine
- DH, dorsal horn
- DMH, dorsomedial hypothalamus
- DRG, dorsal-root ganglion (ganglia)
- EC50, 50% effective concentration of an agonist (produces 50% of the maximum possible response)
- EDmax, maximal effective dose (the dose above which no additional improvement in efficacy is obtained)
- GIT, gastrointestinal tract
- HLI, heat loss index
- IC50, 50% of the maximum inhibitory response)
- JNJ-17203212, 4-[3-(trifluoromethyl)-2-pyridinyl]-N-[5-(trifluoromethy l)-2-pyridinyl]-1-piperazinecarboxamide
- KO, knockout
- LC, locus ceruleus
- LPB, lateral parabrachial nucleus
- LPS, lipopolysaccharide
- MnPO, median preoptic nucleus
- MPO, medial preoptic area
- NADA, N-arachidonoyldopamine
- OEA, oleoylethanolamide
- OLDA, N-oleoyldopamine
- OVLT, organum vasculosum of the lamina terminalis
- PG, prostaglandin
- POA, preoptic area of the hypothalamus
- rRPa, rostral raphe pallidus nucleus
- RTX, resiniferatoxin
- SB 366791, 4′-chloro-3-methoxycinnamanilide
- Ta, ambient temperature
- Tb, body temperature
- Tsk, skin temperature
- TRP, transient receptor potential (channel)
- TRPA, ankyrin TRP
- TRPM, melastatin TRP
- TRPV, vanilloid TRP
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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