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

Abstract

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.

• Authors: Carmen De Caro, Roberto Russo, Carmen Avagliano, Claudia Cristiano, Antonio Calignano, Andrea Aramini, Gianluca Bianchini, Marcello Allegretti, Laura Brandolini
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 175 Issue 10 Pg. 1691-1706 (05 2018) ISSN: 1476-5381 [Electronic] England
• PMID: 29485712 (Publication Type: Journal Article)
• Copyright: © 2018 The British Pharmacological Society.

Chemical References

• 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

Topics

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