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

• Published in: International journal of molecular sciences 2022-02, Vol.23 (5), p.2692
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Action potential; Amides; Analgesics - pharmacology; Analgesics - therapeutic use; Animal models; Animals; beta-Lactams; Cold; Cold Temperature; Disease Models, Animal; Dorsal root ganglia; Ganglia, Spinal - physiology; Hypersensitivity; Menthol; Mice; Migraine; Neuralgia - drug therapy; Neuromodulation; Neurons; Oxaliplatin; Pain; Pain perception; Peripheral neuropathy; Rats; Sciatic nerve; Selectivity; Sensory neurons; Sensory Receptor Cells; Transient receptor potential proteins; TRPM Cation Channels
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23052692

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.