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

Br J Pharmacol. 2018 May;175(10):1691-1706. doi: 10.1111/bph.14177. Epub 2018 Apr 14.


Background and purpose: 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.

Experimental approach: In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested.

Key results: 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 resulted in a significant antinociceptive effect in formalin-induced orofacial pain and in chronic constriction injury-induced neuropathic pain, confirming an important role for this channel in pain perception.

Conclusion and implications: Our findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management.

MeSH terms

  • Acute Pain / drug therapy*
  • Acute Pain / metabolism
  • Analgesics / administration & dosage
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Disease Models, Animal*
  • HEK293 Cells
  • Humans
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / metabolism
  • Tetrazoles / administration & dosage
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*
  • Thiazoles / administration & dosage
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • 5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol
  • Analgesics
  • TRPM Cation Channels
  • TRPM8 protein, human
  • Tetrazoles
  • Thiazoles
  • Trpm8 protein, rat