Effects of Topical Gabapentin on Ocular Pain and Tear Secretion.

Dario Rusciano,Rosario Amato,Paola Bagnoli,Massimo Dal Monte,Maurizio Cammalleri,Salvatore Pezzino,Melania Olivieri

doi:10.3389/fphar.2021.671238

Abstract

Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs, are available to alleviate patients’ discomfort. Anesthetic drugs are not indicated, because they may interfere with the neural feedback between the cornea and the lacrimal gland, impairing tear production and lacrimation. Gabapentin (GBT) is a structural analog of gamma-amino butyric acid that has been used by systemic administration to provide pain relief in glaucomatous patients. We have already shown in a rabbit model system that its topic administration as eye drops has anti-inflammatory properties. We now present data on rabbits’ eyes showing that indeed GBT given topically as eye drops has analgesic but not anesthetic effects. Therefore, opposite to an anesthetic drug such as oxybuprocaine, GBT does not decrease lacrimation, but–unexpectedly–even stimulates it, apparently through the upregulation of acetylcholine and norepinephrine, and by induction of aquaporin 5 (AQP5) expression in the lacrimal gland. Moreover, data obtained in vitro on a primary human corneal epithelial cell line also show direct induction of AQP5 by GBT. This suggests that corneal cells might also contribute to the lacrimal stimulation promoted by GBT and participate with lacrimal glands in the restoration of the tear film, thus reducing friction on the ocular surface, which is a known trigger of ocular pain. In conclusion, GBT is endowed with analgesic, anti-inflammatory and secretagogue properties, all useful to treat neuropathic pain of the ocular surface, especially in case of DED.

Highlights

Neural regulation plays an integral role in maintaining ocular surface homeostasis by tightly controlling lacrimal gland secretion of tear film containing water, electrolytes and a variety of proteins (Dartt, 2009)
We have shown that topical GBT attenuates ocular pain in a rabbit model of corneal injury induced by formaldehyde increased aquaporin 5 (AQP5) levels to reach about a 2-fold increase within 120 min after instillation
Whether GBT-induced upregulation of AQP5 might be coupled to the PKA/CREB pathway was investigated

Summary

Introduction

Neural regulation plays an integral role in maintaining ocular surface homeostasis by tightly controlling lacrimal gland secretion of tear film containing water, electrolytes and a variety of proteins (Dartt, 2009). Disruption of ocular surface homeostasis as induced by altered activity of the feedback loop between the corneal surface and the lacrimal gland causes disturbing effects of which ocular pain is a major component. Sensory afferents from the nerve endings on the corneal surface stimulate efferent sympathetic and parasympathetic fibers of the facial nerve that innervate the lacrimal gland via feedback loops between the ocular surface, lacrimal gland and brain. A disturbance of the neural feedback loops between the ocular surface and lacrimal glands can contribute to corneal diseases such as dry eye disease (DED), in which both nociceptive and neuroptahic pain may be involved (Galor et al, 2015)

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Results

Conclusion