The TRPV1 Channel in Normal Thermoregulation: What Have We Learned from Experiments Using Different Tools?

Garami, András; Almeida, Maria Camila; Nucci, Tatiane B.; Hew‐Butler, Tamara; Soriano, Renato Nery; Pákai, Eszter; Nakamura, Kazuhiro; Morrison, Shaun F.; Romanovsky, Andrej A.

doi:10.1002/9780470588284.ch14

Cited by 2 publications

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“…Potent and selective pharmacological antagonists constitute, arguably, the best tool for revealing tonically active physiological mechanisms . Indeed, an antagonist blocks only processes that already occur in the body.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, a pharmacological agonist may produce effects that never occur under natural conditions, because an endogenous agonist may not exist at all, or it may never reach the relevant target at the concentration required. Using genetic models can be tricky as well, because such models are often ridden with multiple processes of chronic genetic and functional compensation . In the past, using the TRPV1 antagonist AMG0347, we have revealed the “unusual” thermoregulatory reflexes, which adjust the activity of autonomic thermoeffectors in rats (non‐shivering thermogenesis and tail‐skin vasoconstriction) not to the T b , but to the level of pH in yet unidentified abdominal organs, perhaps viscera or muscles .…”

Section: Discussionmentioning

confidence: 99%

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TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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Effect of capsaicin on thermoregulation: an update with new aspects

Szolcsányi

2015

Temperature

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Capsaicin, a selective activator of the chemo- and heat-sensitive transient receptor potential (TRP) V1 cation channel, has characteristic feature of causing long-term functional and structural impairment of neural elements supplied by TRPV1/capsaicin receptor. In mammals, systemic application of capsaicin induces complex heat-loss response characteristic for each species and avoidance of warm environment. Capsaicin activates cutaneous warm receptors and polymodal nociceptors but has no effect on cold receptors or mechanoreceptors. In this review, thermoregulatory features of capsaicin-pretreated rodents and TRPV1-mediated neural elements with innocuous heat sensitivity are summarized. Recent data support a novel hypothesis for the role of visceral warmth sensors in monitoring core body temperature. Furthermore, strong evidence suggests that central presynaptic nerve terminals of TRPV1-expressing cutaneous, thoracic and abdominal visceral receptors are activated by innocuous warmth stimuli and capsaicin. These responses are absent in TRPV1 knockout mice. Thermoregulatory disturbance induced by systemic capsaicin pretreatment lasts for months and is characterized by a normal body temperature at cool environment up to a total dose of 150 mg/kg s.c. Upward differential shift of set points for activation vasodilation, other heat-loss effectors and thermopreference develops. Avoidance of warm ambient temperature (35°C, 40°C) is severely impaired but thermopreference at cool ambient temperatures (Tas) are not altered. TRPV1 knockout or knockdown and genetically altered TRPV1, TRPV2 and TRPM8 knockout mice have normal core temperature in thermoneutral or cool environments, but the combined mutant mice have impaired regulation in warm or cold (4°C) environments. Several lines of evidence support that in the preoptic area warmth sensitive neurons are activated and desensitized by capsaicin, but morphological evidence for it is controversial. It is suggested that these neurons have also integrator function. Fever is enhanced in capsaicin-desensitized rats and the inhibition observed after pretreatment with low i.p. doses does not support in the light of their warmth sensitivity the concept that abdominal TRPV1-expressing nerve terminals serve as nonthermal chemosensors for reference signals in thermoregulation.

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The TRPV1 Channel in Normal Thermoregulation: What Have We Learned from Experiments Using Different Tools?

Cited by 2 publications

References 180 publications

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

Effect of capsaicin on thermoregulation: an update with new aspects

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