TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease

• Published in: International journal of molecular sciences Vol. 21; no. 22; pp. 8756 - 21
• Main Authors: Fakih, Darine, Baudouin, Christophe, Réaux-Le Goazigo, Annabelle, Mélik Parsadaniantz, Stéphane
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-11-2020; MDPI
• Subjects: Administration, Ophthalmic; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Cold; Cold Temperature; Cornea; Cornea - drug effects; Cornea - metabolism; Cornea - physiopathology; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - metabolism; Disease Models, Animal; dry eye; Dry Eye Syndromes - complications; Dry Eye Syndromes - drug therapy; Dry Eye Syndromes - genetics; Dry Eye Syndromes - metabolism; electrophysiology; Evaluation; Evoked Potentials, Somatosensory - drug effects; Eye diseases; Ganglia, Parasympathetic - drug effects; Ganglia, Parasympathetic - metabolism; Ganglia, Parasympathetic - physiopathology; Gene expression; Gene Expression Regulation; Glands; Harderian Gland - surgery; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Hyperalgesia - genetics; Hyperalgesia - metabolism; Inflammation; Interleukin-18 - genetics; Interleukin-18 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Lacrimal Apparatus - surgery; Life Sciences; Male; Mice; Mice, Inbred C57BL; Neuralgia - drug therapy; Neuralgia - etiology; Neuralgia - genetics; Neuralgia - metabolism; Nicotinic Acids - pharmacology; Pain; Pain perception; Pain sensitivity; Prostaglandin-E Synthases - genetics; Prostaglandin-E Synthases - metabolism; Signs and symptoms; Thiophenes - pharmacology; Transient receptor potential proteins; Trigeminal ganglion; Trigeminal Ganglion - drug effects; Trigeminal Ganglion - metabolism; Trigeminal Ganglion - physiopathology; TRPM Cation Channels - antagonists & inhibitors; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; TRPM8 antagonist; TRPM8 antagonist; electrophysiology; dry eye; cornea; inflammation; Electrophysiology; Cornea; Inflammation; Dry eye
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228756

Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by the excision of extra-orbital lacrimal and Harderian glands. M8-B was topically administered twice a day from day 7 until day 21 after surgery. Cold and mechanical corneal sensitivities and spontaneous ocular pain were monitored at day 21. Ongoing and cold-evoked ciliary nerve activities were next evaluated by electrophysiological multi-unit extracellular recording. Corneal inflammation and expression of genes related to neuropathic pain and inflammation were assessed in the trigeminal ganglion. We found that DED mice developed a cold allodynia consistent with higher TRPM8 mRNA expression in the trigeminal ganglion (TG). Chronic M8-B instillations markedly reversed both the corneal mechanical allodynia and spontaneous ocular pain commonly associated with persistent DED. M8-B instillations also diminished the sustained spontaneous and cold-evoked ciliary nerve activities observed in DED mice as well as inflammation in the cornea and TG. Overall, our study provides new insight into the effectiveness of TRPM8 blockade for alleviating corneal pain syndrome associated with severe DED, opening a new avenue for ocular pain management.