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.

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

De Caro, Carmen;Russo, Roberto
;
Avagliano, Carmen;Cristiano, Claudia;Calignano, Antonio;
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. 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.
File in questo prodotto:
File Dimensione Formato  
Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat.pdf

non disponibili

Licenza: Dominio pubblico
Dimensione 1.26 MB
Formato Adobe PDF
1.26 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/717932
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 28
  • ???jsp.display-item.citation.isi??? 28
social impact