PMID- 29485712
OWN - NLM
STAT- MEDLINE
DCOM- 20190806
LR  - 20210109
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 175
IP  - 10
DP  - 2018 May
TI  - Antinociceptive effect of two novel transient receptor potential melastatin 8 
      antagonists in acute and chronic pain models in rat.
PG  - 1691-1706
LID - 10.1111/bph.14177 [doi]
AB  - 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.
CI  - (c) 2018 The British Pharmacological Society.
FAU - De Caro, Carmen
AU  - De Caro C
AD  - Department of Pharmacy, University of Naples Federico II, Naples, Italy.
AD  - Department of Science of Health, School of Medicine and Surgery, University of 
      Catanzaro, Catanzaro, Italy.
FAU - Russo, Roberto
AU  - Russo R
AUID- ORCID: 0000-0001-5950-1617
AD  - Department of Pharmacy, University of Naples Federico II, Naples, Italy.
FAU - Avagliano, Carmen
AU  - Avagliano C
AD  - Department of Pharmacy, University of Naples Federico II, Naples, Italy.
FAU - Cristiano, Claudia
AU  - Cristiano C
AD  - Department of Pharmacy, University of Naples Federico II, Naples, Italy.
FAU - Calignano, Antonio
AU  - Calignano A
AD  - Department of Pharmacy, University of Naples Federico II, Naples, Italy.
FAU - Aramini, Andrea
AU  - Aramini A
AD  - Dompe Farmaceutici S.p.A., L'Aquila, Italy.
FAU - Bianchini, Gianluca
AU  - Bianchini G
AD  - Dompe Farmaceutici S.p.A., L'Aquila, Italy.
FAU - Allegretti, Marcello
AU  - Allegretti M
AD  - Dompe Farmaceutici S.p.A., L'Aquila, Italy.
FAU - Brandolini, Laura
AU  - Brandolini L
AD  - Dompe Farmaceutici S.p.A., L'Aquila, Italy.
LA  - eng
PT  - Journal Article
DEP - 20180414
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol)
RN  - 0 (Analgesics)
RN  - 0 (TRPM Cation Channels)
RN  - 0 (TRPM8 protein, human)
RN  - 0 (Tetrazoles)
RN  - 0 (Thiazoles)
RN  - 0 (Trpm8 protein, rat)
MH  - Acute Pain/*drug therapy/metabolism
MH  - Analgesics/administration & dosage/chemistry/*pharmacology
MH  - Animals
MH  - Chronic Pain/*drug therapy/metabolism
MH  - *Disease Models, Animal
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TRPM Cation Channels/*antagonists & inhibitors/metabolism
MH  - Tetrazoles/administration & dosage/chemistry/*pharmacology
MH  - Thiazoles/administration & dosage/chemistry/*pharmacology
PMC - PMC5913409
EDAT- 2018/02/28 06:00
MHDA- 2019/08/07 06:00
PMCR- 2019/05/01
CRDT- 2018/02/28 06:00
PHST- 2017/08/03 00:00 [received]
PHST- 2018/01/23 00:00 [revised]
PHST- 2018/02/05 00:00 [accepted]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2019/08/07 06:00 [medline]
PHST- 2018/02/28 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - BPH14177 [pii]
AID - 10.1111/bph.14177 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2018 May;175(10):1691-1706. doi: 10.1111/bph.14177. Epub 2018 Apr 
      14.