Trends in Pharmacological Sciences
OpinionBody-temperature maintenance as the predominant function of the vanilloid receptor TRPV1
Section snippets
History of the vanilloid receptor TRPV1
Capsaicin modulation of body temperature was documented even before the prediction of a receptor for it [1]. Capsaicin causes a drop in body temperature (hypothermia) in multiple species including humans [2] and also causes pain in humans and pain-like behavior in preclinical species [3]. Resiniferatoxin (RTX), the ultra-potent functional analog of capsaicin, also elicits the same effects 3, 4. Existence of a capsaicin receptor was proved with the development of a [3H]RTX-binding assay that
Agonists of TRPV1 cause hypothermia
The first documented evidence of capsaicin causing hypothermia in a dog after intragastric administration of an oily extract from the Hungarian red pepper was reported in 1878 [1]. Extensive studies were later followed that revealed the role for capsaicin in thermoregulation (reviewed in Refs 2, 23). Capsaicin caused hypothermia when administered by a variety of routes that include oral, intraperitoneal (i.p.) and intracerebral administration in a wide variety of animals such as mice, rats,
TRPV1 channels are tonically active in vivo and regulate body temperature
Although TRPV1 agonists cause hypothermia, until recently it was not known whether TRPV1 is tonically active or even whether it is involved in body-temperature regulation 12, 14, 15. Further, TRPV1-knockout mice did not showed substantial impairment or deficiencies in their thermoregulation 27, 28, an observation that masked the role of TRPV1 in body-temperature maintenance.
Possible mechanisms of tonic TRPV1 activation
Anandamide, oleoyldopamine, N-arachidonyl dopamine, 12-hydroperoxyeicosatetraenoic acid and low pH all were reported to be the putative endogenous agonists of TRPV1 (reviewed in Refs 10, 11, 29) based on their ability to: (i) activate recombinantly expressed TRPV1 channels, (ii) replace [3H]RTX binding to cell membranes prepared from TRPV1-expressing cell lines or (ii) cause release of calcitonin-gene-related peptide and substance P in a TRPV1-dependent manner. Phosphorylation of certain
The role of TRPV1 in thermoregulation can be compensated
Efforts to correlate hyperthermia with the time course of TRPV1-antagonist plasma-concentration levels in rats revealed that antagonists induce transient hyperthermia [15]. In several experiments, as little as 33.8 ± 6.8 ng ml−1 plasma concentration of AMG8163 caused hyperthermia in rats. In one experiment, 10 mg kg−1 of AMG8163 caused hyperthermia only for ∼20 h, whereas plasma levels of AMG8163 at 24 h post administration were significantly higher than the minimum plasma concentration necessary to
TRPV1 agonists and antagonists use the same thermoeffector mechanisms to alter body temperature
The heat-loss index {HLI = (skin temperature [Ts] – ambient temperature [Ta])/(body temperature [Tb] − Ta)} was used as a measure of vasoconstriction or vasodilation of smooth muscles in arterioles, whereas thermogenesis was measured by oxygen consumption (VO2; an increase indicates increased metabolic heat production and a decrease indicates decreased heat production) in the studies mentioned here.
Site of action for TRPV1 thermoregulation is outside of the blood–brain barrier
It is believed that thermoregulation is controlled by the brain regions both within and outside of the blood–brain barrier (BBB). It has been established that warm-sensitive neurons in the preoptic-anterior hypothalamus (PO-AH) serve as first efferent neurons for several autonomic thermoeffectors and, thus, have a principal role in the central control of thermoregulation (for reviews see Refs 2, 22, 33). For example, the presence of capsaicin-sensitive structures in the preoptic and in other
Tonically active TRPV1 channels are one part of the counterbalancing regulators that maintain body temperature
Based on the heat or cold activation, a group of TRP channels expressed in the sensory nerve endings in the skin have been proposed as ‘thermoTRP’ channels to mediate thermosensation 39, 40. Importantly, the studies covered here unequivocally demonstrated that tonically active TRPV1 channels are involved in thermoregulation, in particular that TRPV1 has an important role in maintaining normal body temperature. It is not known whether other thermoTRP channels such as TRPA1, TRPM8, TRPV3 and
Concluding remarks
Does TRPV1 involvement in thermoregulation impede clinical development of TRPV1 antagonists? It is still an open question. AMG 517 clinical evaluations were discontinued because AMG 517 elicited marked and persistent hyperthermia in patients who have undergone molar extraction [17]. Although antipyretics suppressed TRPV1-antagonist-induced hyperthermia in rats completely [16], AMG-517-induced hyperthermia in dental-pain patients was not suppressed by antipyretics satisfactorily [17]. Currently,
Conflict-of-interest statement
The author is an employee of Amgen (www.amgen.com).
Personal note
It is estimated that >55 biotechnology and pharmaceutical companies are pursuing TRPV1 modulators (agonists and antagonists) as potential therapeutics. Collectively, the cost of lead optimization and the generation of clinical candidates and their evaluation in proof-of-concept and Phase II and III studies (of both agonists and antagonists) seems to reach a staggering $1 billion dollars, making TRPV1 the most expensive preclinical target for the drug-discovery industry. Despite this enormous
References (50)
Capsaicin and central control of thermoregulation
Pharmacol. Ther.
(1984)- et al.
Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper
Neuroscience
(1989) - et al.
Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor
Life Sci.
(1990) - et al.
The TRPV1 receptor and nociception
Semin. Cell Dev. Biol.
(2006) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans
Pain
(2008)TRPV1: a therapeutic target for novel analgesic drugs?
Trends Mol. Med.
(2006)Forty years in capsaicin research for sensory pharmacology and physiology
Neuropeptides
(2004)Thermoregulatory effects of resiniferatoxin in the rat
Eur. J. Pharmacol.
(1994)Neurobehavioral activity in mice of N-vanillyl-arachidonyl-amide
Eur. J. Pharmacol.
(2000)Attenuated fever response in mice lacking TRPV1
Neurosci. Lett.
(2005)
Neurophysiological and thermoregulatory effects of capsaicin
Brain Res. Bull.
Specific binding of [3H]resiniferatoxin by human and rat preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus membrane preparations
Life Sci.
Responses of anterior hypothalamic-preoptic thermosensitive neurons to locally applied capsaicin
Neuropharmacology
Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain
Brain Res. Mol. Brain Res.
Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects
Bioorg. Med. Chem. Lett.
Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development
Bioorg. Med. Chem. Lett.
Beiträge zur physiologischen Wirkung der Bestandteile des Capsicum annuum
Arch. Exp. Path. Pharmak.
Vanilloid (capsaicin) receptors and mechanisms
Pharmacol. Rev.
[3H]resiniferatoxin binding by the vanilloid receptor: species-related differences, effects of temperature and sulfhydryl reagents
Naunyn Schmiedebergs Arch. Pharmacol.
The capsaicin receptor: a heat-activated ion channel in the pain pathway
Nature
Impaired nociception and pain sensation in mice lacking the capsaicin receptor
Science
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia
Nature
The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept
Nat. Rev. Drug Discov.
Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors
J. Neurosci.
Cited by (166)
Neuroprotective effect of transient receptor potential Vanilloid 1 agonist capsaicin in Alzheimer's disease model induced with okadaic acid
2023, International ImmunopharmacologyMenthol relieves acid reflux inflammation by regulating TRPV1 in esophageal epithelial cells
2020, Biochemical and Biophysical Research CommunicationsIn vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (TRPV1) inhibitor GRTE16523
2020, European Journal of PharmacologyThe investigation of allosteric regulation mechanism of analgesic effect using SD rat taste bud tissue biosensor
2019, Biosensors and BioelectronicspH-dependent modulation of TRPV1 by modality-selective antagonists
2023, British Journal of Pharmacology