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

Darine Fakih,Christophe Baudouin,Annabelle Réaux-Le Goazigo,Stéphane Mélik Parsadaniantz

doi:10.3390/ijms21228756

Abstract

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.

Highlights

Dry eye disease (DED) is a chronic ocular disease characterized by dryness, discomfort, burning sensation, and pain in the eye [1]
We found in an ex vivo eye preparation of DED mice that single application of transient receptor potential melastatin 8 (TRPM8) antagonist (M8-B) at 20 and 30 μM decreased cold-evoked ciliary nerve activity compared to a saline-treated DED group
We further found in vivo that chronic topical instillations of (20 μM) M8-B twice daily for 15 days in DED mice decreased (1) the spontaneous and cold-evoked activity of corneal nerve in ex vivo eyes preparations, (2) corneal inflammation, (3) expression of genes related to neuropathic and inflammatory pain in the trigeminal ganglion (TG), and (4) corneal mechanical allodynia and spontaneous ocular pain

Summary

Introduction

Dry eye disease (DED) is a chronic ocular disease characterized by dryness, discomfort, burning sensation, and pain in the eye [1]. Genetic deletion of TRPM8 revealed that TRPM8−/− mice are deficient in unpleasant cold sensitivity, confirming the implication of this channel in cold-pain sensation [17,18,19]. Cold allodynia is a common feature of neuropathic pain [20,21] and numerous preclinical studies demonstrated the essential function of TRPM8 in neuropathic pain perception [22,23,24,25,26]. In this regard, pharmacological studies have demonstrated that TRPM8 ligands or inhibitors/blockers attenuate pain sensation in numerous somatic pain models. TRPM8 antagonists were shown to efficiently alleviate acute and chronic pain [27,28,29,30], whereas the TRPM8 agonist may present significant antiallodynic activity through an excessive activation of TRPM8, leading to its downregulation [31]

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