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Martín-Escura, Cristina; Medina-Peris, Alicia; Spear, Luke A.; de la Torre Martínez, Roberto; Olivos-Oré, Luis A.; Barahona, María Victoria; González-Rodríguez, Sara; Fernández-Ballester, Gregorio; Fernández-Carvajal, Asia; Artalejo, Antonio R.; Ferrer-Montiel, Antonio; González-Muñiz, Rosario

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

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  • Media type: E-Article
  • Title: β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models
  • Contributor: Martín-Escura, Cristina; Medina-Peris, Alicia; Spear, Luke A.; de la Torre Martínez, Roberto; Olivos-Oré, Luis A.; Barahona, María Victoria; González-Rodríguez, Sara; Fernández-Ballester, Gregorio; Fernández-Carvajal, Asia; Artalejo, Antonio R.; Ferrer-Montiel, Antonio; González-Muñiz, Rosario
  • imprint: MDPI AG, 2022
  • Published in: International Journal of Molecular Sciences
  • Language: English
  • DOI: 10.3390/ijms23052692
  • ISSN: 1422-0067
  • Keywords: Inorganic Chemistry ; Organic Chemistry ; Physical and Theoretical Chemistry ; Computer Science Applications ; Spectroscopy ; Molecular Biology ; General Medicine ; Catalysis
  • Origination:
  • Footnote:
  • Description: <jats:p>Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.</jats:p>
  • Access State: Open Access