Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

British Journal of Pharmacology
Carmen De CaroLaura Brandolini

Abstract

Transient receptor potential (TRP) channels are a superfamily of non-selective cation permeable channels involved in peripheral sensory signalling. Animal studies have shown that several TRPs are important players in pain modulation. Among them, the TRP melastatin 8 (TRPM8) has elicited more interest for its controversial role in nociception. This channel, expressed by a subpopulation of sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (TG), is activated by cold temperatures and cooling agents. In experimental neuropathic pain models, an up-regulation of this receptor in DRG and TG has been observed, suggesting a key role for TRPM8 in the development and maintenance of pain. Consistent with this hypothesis, TRPM8 knockout mice are less responsive to pain stimuli. In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested. Two potent and selective TRPM8 antagonists with distinct pharmacokinetic profiles, DFL23693 and DFL23448, have been fully characterized in vitro. In vivo studies in well-established models, namely, the wet-dog shaking test and changes in body temperature, confirmed their ability to block the TRPM8 channel. Finally, TRPM8 blockage ...Continue Reading

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Citations

May 31, 2019·International Journal of Molecular Sciences·Rosario González-MuñizIsabel Gómez-Monterrey
Nov 11, 2019·International Journal of Molecular Sciences·Carmen De CaroRoberto Russo
Aug 9, 2020·Pain Reports·Jun-Hui YuanStephen G Waxman
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Nov 25, 2020·International Journal of Molecular Sciences·Darine FakihStéphane Mélik Parsadaniantz
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Aug 24, 2018·Biochemical Pharmacology·Carmen Del RíoEduardo Muñoz
Nov 16, 2021·Frontiers in Neuroscience·Tom Vincent-DospitalKnut Jørgen Måløy

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