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

Abstract

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.

TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

“…Ten years ago already, several TRPV1 antagonists have entered clinical trials, including ABT-102, SB-705498, AMG-517, MK2295 and GRC-6211 [114], however, the major setback in the development of TRPV1 antagonists for the treatment of chronic pain was an elevation of the body temperature. Attempts to develop TRPV1 antagonists without causing hyperthermia are in the focus of recent pharmacological research [115].…”

The opioid crisis and … reconsidering the use of drugs that affect body temperature

“…Additionally, blockade of TRPV1 was shown to lead to hyperthermia, a potentially dangerous effect that inhibited further development of this class of compounds (for a review, see ref. 4). More recent evidence reveals that, in some cases, TRPV1 blockade also produced hypothermia [4].…”

“…4). More recent evidence reveals that, in some cases, TRPV1 blockade also produced hypothermia [4]. The clinical question of whether blocking TRPV1 could produce analgesic benefit for patients was thus never fully answered.…”

Manipulating transient receptor potential vanilloid 1 antagonists: How to cool down a hot molecule?

“…In this issue of Acta Physiologica , Romanovsky et al report two TRPV1 antagonists that paradoxically induce hypothermia . When administered peripherally, the newly synthetized compound, A‐1165901, and the previously reported molecule, AMG7905, both triggered vasodilatation, an effect similar to that of application of capsaicin.…”

“…Although a number of small molecule TRPV1 antagonists have been advanced into clinical trials, thus far, none has progressed beyond Phase II due to on‐target side effects such as a febrile reaction . In this issue of Acta Physiologica , Romanovsky et al report two TRPV1 antagonists that paradoxically induce hypothermia in experimental animals, potentially opening a new avenue for drug development …”