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

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 lea...

Descripción completa

Detalles Bibliográficos
Autores: Martín Escura, Cristina, Medina Peris, Alicia, Spear, Luke A., de la Torre Martínez, Roberto, Olivos Ore, Luis Alcides, Barahona Gomáriz, María Victoria, González Rodríguez de Castro, Sara, Fernández Ballester, Gregorio, Fernández Carvajal, Asia, Rodríguez Artalejo, Antonio, Ferrer Montiel, Antonio, González Muñiz, Rosario
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/72502
Acceso en línea:https://hdl.handle.net/20.500.14352/72502
Access Level:acceso abierto
Palabra clave:TRPM8 channels
antagonist
β–lactam
oxaliplatin-induced peripheral neuropathy
CCI chronic neuropathic
nociception
NTG-induced hyperesthesia
Farmacología veterinaria
3109.08 Farmacología
Descripción
Sumario: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.

Similares en LA Referencia