Characterization of New TRPM8 Modulators in Pain Perception

• Published in: International journal of molecular sciences 2019-11, Vol.20 (22), p.5544
• Main Authors: De Caro, Carmen, Cristiano, Claudia, Avagliano, Carmen, Bertamino, Alessia, Ostacolo, Carmine, Campiglia, Pietro, Gomez-Monterrey, Isabel, La Rana, Giovanna, Gualillo, Oreste, Calignano, Antonio, Russo, Roberto
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics - chemistry; Analgesics - pharmacology; Animal models; Animals; Body temperature; Channel gating; Chemical compounds; Cold; Depletion; Desensitization; Diabetes mellitus; Disease Models, Animal; Dorsal root ganglia; Genital tract; local application; Male; Menthol; Mice; Nervous system; Neuromodulation; neuropathic pain; Neurosciences; Organic chemistry; orofacial pain; Oxaliplatin; Pain; Pain - drug therapy; Pain - metabolism; Pain - pathology; Pain - physiopathology; Pain perception; Pain Perception - drug effects; Perception; Phosphatidylinositol 4,5-diphosphate; Rats; Rats, Sprague-Dawley; Rodents; Sensory neurons; Streptozocin; systemic administration; Transient receptor potential proteins; TRPM Cation Channels - antagonists & inhibitors; TRPM Cation Channels - metabolism; trpm8
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20225544

Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca -dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.