Ocular pain is a core symptom of inflammatory or traumatic disorders affecting the anterior segment. To date, the management of chronic ocular pain remains a therapeutic challenge in ophthalmology. The main endogenous opioids (enkephalins) play a key role in pain control but exhibit only transient analgesic effects due to their rapid degradation. The aim of this study was to explore the antinociceptive and anti-inflammatory effects of topical administration of PL265 (a dual enkephalinase inhibitor) on murine models of corneal pain. On healthy corneas, chronic PL265 topical administration did not alter corneal integrity nor modify corneal mechanical and chemical sensitivity. Then, on murine models of corneal pain, we showed that repeated instillations of PL265 (10 mM) significantly reduced corneal mechanical and chemical hypersensitivity. PL265-induced corneal analgesia was completely antagonized by naloxone methiodide, demonstrating that PL265 antinociceptive effects were mediated by peripheral corneal opioid receptors. Moreover, flow cytometry (quantification of CD11b+ cells) and in vivo confocal microscopy analysis revealed that instillations of PL265 significantly decreased corneal inflammation in a corneal inflammatory pain model. Chronic PL265 topical administration also decreased Iba1 and neuronal injury marker (ATF3) staining in the nucleus of primary sensory neurons of ipsilateral trigeminal ganglion. These results open a new avenue for ocular pain treatment based on the enhancement of endogenous opioid peptides' analgesic effects in tissues of the anterior segment of the eye. Dual enkephalinase inhibitor PL265 seems to be a promising topical treatment for safe and effective alleviation of ocular pain and inflammation.
Dual enkephalinase inhibitors are a promising topical medication for the safe and efficacious alleviation of corneal pain and inflammation.
aINSERM UMR S 968, CNRS UMR 7210, Institut de la Vision, Sorbonne Université, Paris, France
bPharmaleads SA, Paris, France
cDHU Sight Restore, INSERM-DGOS CIC 1423, CHNO des Quinze-Vingts, Paris, France
Corresponding author. Address: Département Thérapeutique, Institut de la Vision, équipe S12, 17 rue Moreau, 75012 Paris, France. Tel:. +33153462572. E-mail address: email@example.com (S. Melik Parsadaniantz).
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Received February 08, 2018
Received in revised form September 28, 2018
Accepted October 11, 2018