Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice

Fanny Joubert (1) , Adrian Guerrero-Moreno (1) , Darine Fakih (1) , Elodie Reboussin (1) , Claire Gaveriaux-Ruff (2, 3) , Maria Carmen Acosta (4, 5) , Juana Gallar (4, 5) , José Alain Sahel (1, 6, 7, 8) , Laurence Bodineau (9) , Christophe Baudouin (1, 6, 10) , William Rostène (1) , Stéphane Melik-Parsadaniantz (1) , Annabelle Réaux-Le Goazigo (1)

1 Institut de la Vision
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 ESBS - Ecole Supérieure de Biotechnologie de Strasbourg
4 UMH - Universidad Miguel Hernández [Elche]
5 CSIC - Consejo Superior de Investigaciones Científicas [Spain]
6 CHNO - Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts
7 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
8 University of Pittsburgh School of Medicine
9 UMRS 1158 - Neurophysiologie Respiratoire Expérimentale et Clinique
10 Service d'ophtalmologie [CHU Ambroise Paré]

Corneal pain is considered to be a core symptom of ocular surface disruption and inflammation. The management of this debilitating condition is still a therapeutic challenge. Recent evidence supports a role of the opioid system in the management of corneal nociception. However, the functional involvement of the mu opioid receptor (MOR) underlying this analgesic effect is not known. We first investigated the expression of the MOR in corneal nerve fibers and trigeminal ganglion (TG) neurons in control mice and a mouse model of corneal inflammatory pain. We then evaluated the anti-nociceptive and electrophysiological effects of DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol] enkephalin), a MOR-selective ligand. MOR immunoreactivity was detected in corneal nerve fibers and primary afferent neurons of the ophthalmic branch of the TG of naive mice. MOR expression was significantly higher in both structures under conditions of inflammatory corneal pain. Topical ocular administration of DAMGO strongly reduced both the mechanical (von Frey) and chemical (capsaicin) corneal hypersensitivity associated with inflammatory ocular pain. Repeated instillations of DAMGO also markedly reversed the elevated spontaneous activity of the ciliary nerve and responsiveness of corneal polymodal nociceptors that were observed in mice with corneal pain. Finally, these DAMGO-induced behavioral and electrophysiological responses were totally blunted by the topical application of naloxone methiodide, an opioid receptor antagonist. Overall, these results provide evidence that topical pharmacological MOR activation may constitute a therapeutic target for the treatment of corneal pain and improve corneal nerve function to alleviate chronic pain.

Mots clés: Corneal pain; Electrophysiology; Inflammation; Opioid receptor

Domaines: Sciences du Vivant [q-bio]

Fanny Joubert, Adrian Guerrero-Moreno, Darine Fakih, Elodie Reboussin, Claire Gaveriaux-Ruff, et al.. Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice. Biomedicine and Pharmacotherapy, 2020, 132, pp.110794. ⟨10.1016/j.biopha.2020.110794⟩. ⟨hal-03045488⟩