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Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2018 May; Vol. 175 (10), pp. 1691-1706. Date of Electronic Publication: 2018 Apr 14. - Publication Year :
- 2018
-
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.<br />Experimental Approach: In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested.<br />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.<br />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.<br /> (© 2018 The British Pharmacological Society.)
- Subjects :
- Acute Pain metabolism
Analgesics administration & dosage
Analgesics chemistry
Animals
Chronic Pain metabolism
HEK293 Cells
Humans
Male
Rats
Rats, Sprague-Dawley
TRPM Cation Channels metabolism
Tetrazoles administration & dosage
Tetrazoles chemistry
Thiazoles administration & dosage
Thiazoles chemistry
Acute Pain drug therapy
Analgesics pharmacology
Chronic Pain drug therapy
Disease Models, Animal
TRPM Cation Channels antagonists & inhibitors
Tetrazoles pharmacology
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 175
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 29485712
- Full Text :
- https://doi.org/10.1111/bph.14177