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

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.

Fig. 1.

A schematic of the afferent (the left portion of the figure) and efferent (the right portion) neural pathways underlying the BAT thermogenesis and cutaneous vasoconstriction responses to innocuous thermal stimulation of the skin. IML, intermediolateral column; SG, sympathetic ganglia. For detailed descriptions, see section II.B.

Fig. 2.

CAP- or RTX-induced hypothermia occurs neither in Trpv1 KO mice nor in transgenic mice with the Trpv1 gene silenced by short hairpin RNAs. A, effects of CAP (1 mg/kg s.c.) on colonic temperature in Trpv1 KO and control mice. B, effects of RTX (500 ng/kg i.p.) on abdominal temperature in Trpv1 KO and control mice. C, effects of CAP (3 mg/kg i.p.) on colonic temperature in transgenic (Trpv1-silenced) and control mice. In A and B, the insets show whole-cell patch-clamp recordings from cultured DRG neurons of Trpv1 KO and control mice. Cells from the KO animals did not respond with a typical inward cationic current to CAP (A) or RTX (B). The inset in C shows changes in the intracellular Ca²⁺ concentration in cultured DRG neurons from transgenic (Trpv1-silenced) and normal mice. Cells from the transgenic animals did not respond to CAP. [A and the inset in B are modified from Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, and Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313. Copyright © 2000 American Association for the Advancement of Science. The graph in B is modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. C is modified from Christoph T, Bahrenberg G, De Vry J, Englberger W, Erdmann VA, Frech M, Kögel B, Röhl T, Schiene K, Schröder W, et al. (2008); Investigation of TRPV1 loss-of-function phenotypes in transgenic shRNA expressing and knockout mice. Mol Cell Neurosci 37:579–589. Copyright © 2008 Elsevier. All images used with permission.].

Fig. 3.

Recruitment of autonomic and behavioral thermoeffectors in the hypothermic response of rats to RTX. A, peripheral administration of RTX (500 ng/kg i.v.) causes hypothermia (a decrease in colonic temperature), tail skin vasodilation (an increase in the HLI), and an inhibition of thermogenesis (a reduction in oxygen consumption). The HLI is calculated according to the formula: HLI = (T_sk − T_a)/(T_b − T_a); it changes between 0 (maximal skin vasoconstriction) and some value that depends on the tail thermocouple position but is smaller than 1.0 (maximal vasodilation) (Romanovsky et al., 2002). A reports original data obtained in catheterized (jugular vein) male Wistar rats placed in a thermocouple-respirometry setup; all the methods involved are described elsewhere (Steiner et al., 2007). The protocol was approved by the St. Joseph's Hospital and Medical Center Animal Care and Use Committee. The data are shown as means ± S.E.; the number of rats in each group was five. B, RTX treatment (500 ng/kg i.v.) lowers abdominal temperature and induces cold-seeking behavior (a decrease in the preferred T_a in a thermogradient apparatus). [B is modified from Almeida MC, Steiner AA, Branco LG, and Romanovsky AA (2006) Cold-seeking behavior as a thermoregulatory strategy in systemic inflammation. Eur J Neurosci 23:3359–3367. Copyright © 2006 Wiley-Blackwell. Used with permission.]

Fig. 4.

The effect of heat exposure (41°C) on rectal temperature of adult rats that received a high dose of CAP (200–300 mg/kg s.c.) as neonates and of their littermates that were not treated with CAP. The CAP-desensitized rats have a severe impairment of heat-defense responses and, consequently, exhibit a much greater increase in T_b. [Modified from Hori T and Tsuzuki S (1981) Thermoregulation in adult rats which have been treated with capsaicin as neonates. Pflugers Arch 390:219–223. Copyright © 1981 Springer Science+Business Media. Used with permission.]

Fig. 5.

TRPV1 antagonists cause hyperthermia in different species. A, effect of AMG0347 (500 μg/kg i.p.) or its vehicle on abdominal temperature in mice at a neutral T_a of 31°C. B, effect of AMG0347 (500 μg/kg i.v.) or its vehicle on colonic temperature in rats at a neutral T_a of 28°C. C, effect of daily administration of AMG 517 (10 mg p.o.) or placebo over days 0 to 6 on tympanic temperature in humans at room temperature. Note that the arrow in C shows just the first day of drug administration. D, effect of AMG 517 (100 μg/kg i.v.) or its vehicle on colonic temperature in rats at a neutral T_a of 26°C. E, effects of JYL 1421 (30 mg/kg p.o.) or its vehicle on T_b (location not specified) in dogs at room temperature. F, effects of JYL 1421 (30 mg/kg p.o.) or its vehicle on T_b (location not specified) in cynomolgus monkeys at room temperature. [A and B are modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. C and D are modified from Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, et al. (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–210. Copyright © 2008 International Association for the Study of Pain (IASP). E and F are modified from Gavva NR, Bannon AW, Surapaneni S, Hovland DN Jr, Lehto SG, Gore A, Juan T, Deng H, Han B, Klionsky L, et al. (2007) The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J Neurosci 27:3366–3374. Copyright © 2007 Society for Neuroscience. All images used with permission.].

Fig. 6.

AMG0347 (500 μg/kg i.v.) causes hyperthermia in control mice, but not in Trpv1 KO mice. [Modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. Used with permission.].

Fig. 7.

Recruitment of autonomic, but not behavioral, thermoeffectors in the hyperthermic response of rats to AMG0347. AMG0347 (50 μg/kg i.v.) was administered to loosely restrained rats either at a low neutral T_a of 24°C (A) or at a subneutral T_a of 17°C (B). In either case, the injections were performed through a preimplanted jugular catheter, from outside the environmental chamber, without disturbing the animals (Steiner et al., 2007). Because the procedure of drug administration did not cause stress, injection of a vehicle alone did not affect colonic temperature. At 24°C, the hyperthermic response to AMG0347 occurred, at least in part, because of tail skin vasoconstriction (a decrease in the HLI). At 17°C, the hyperthermic response to AMG0347 occurred, at least in part, because of thermogenesis activation (an increase in oxygen consumption). AMG0347 (500 μg/kg i.v.) also caused hyperthermia in a thermogradient apparatus (C). In this setup, the procedure for drug administration involved handling, and the injection of vehicle caused stress hyperthermia, but the hyperthermic response to AMG0347 was higher and lasted longer than the response to the vehicle. Even though a high dose of AMG0347 was used in this experiment, thermoregulatory behavior was not recruited, and the drug-injected rats preferred the same T_a as the rats injected with the vehicle. [Modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. Used with permission.].

Fig. 8.

AMG0347 hyperthermia is independent of either basal colonic temperature or basal tail T_sk. AMG0347 (50 μg/kg i.v.) was injected in rats at T_a of 17, 24, or 28°C (A). At all T_a values tested, the drug induced hyperthermic responses of similar magnitude. When the response magnitude (the maximal increase in colonic temperature) for each rat was plotted against its basal (at the time of drug administration) colonic temperature (B) or against its basal T_sk (C), no positive correlation was found. [Modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. Used with permission.]

Fig. 9.

Localized intra-abdominal TRPV1 desensitization abolishes the AMG0347-induced hyperthermia in rats. Shown is the effect of AMG0347 (50 μg/kg i.v.) on colonic temperature of rats pretreated with RTX (20 μg/kg i.p.) or its vehicle 10 days before the experiment. [Modified from Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, et al. (2007) Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27:7459–7468. Copyright © 2007 Society for Neuroscience. Used with permission.].

Fig. 10.

The proposed pathway for tonic inhibition of BAT thermogenesis and skin vasoconstriction by nonthermal activation of visceral TRPV1 channels and proposed mechanisms of the thermoregulatory effects of TRPV1 agonists, TRPV1 desensitization, and TRPV1 antagonists. The proposed pathway (dotted line) is compared with the thermoregulatory pathways activated by innocuous skin warming and cooling (solid lines). On the efferent side (right portion of the figure), neurons in the brain stem and spinal cord structures that are common to all three pathways are omitted (to avoid repetition of Fig. 1). All omitted synapses are excitatory. Abbreviations and symbols are the same as in Fig. 1. We propose that TRPV1 agonists and antagonists act on two neurons: the glutamatergic MnPO neuron within the pathway activated by innocuous warming of the skin and a glutamatergic polymodal visceral DRG neuron. TRPV1 channels on the MnPO neurons are normally closed and are therefore readily affected by TRPV1 agonists but not by antagonists. Channels on the DRG neurons are tonically activated by nonthermal factors and are therefore more susceptible to the action of antagonists. Because TRPV1 agonists affect the MnPO neurons, these neurons lose their function first during desensitization. Higher doses of TRPV1 agonists induce secondary degeneration of warm-sensitive GABA-ergic MPO neurons, an effect that is subject to partial recovery when the desensitizing dose of the agonist is administered in the neonatal period. For further explanations, see sections IV.E.6 and V.A.