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Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1

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Agonists of the transient receptor potential vanilloid type 1 (TRPV1), such as capsaicin, cause pain and a drop in body temperature (hypothermia). Conversely, antagonists of TRPV1 block pain behaviors in rodent models of inflammation, osteoarthritis and cancer. Efforts that evaluate TRPV1 antagonists in on-target challenge models have uncovered that TRPV1 blockade elicits an increase in body temperature (hyperthermia) from rodents to primates, revealing the intimate relationship between the role of TRPV1 in pain and body-temperature maintenance. This evolutionarily conserved function of TRPV1 in body-temperature maintenance became a hurdle for clinical development of one antagonist, AMG 517. However, several other TRPV1 antagonists are currently being evaluated in the clinic and soon-to-be-published results should shed light on the potential of managing antagonist-induced hyperthermia while developing them as therapeutics.

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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

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