Corneal sensory nerve regulation of tear production through stimulation of transient receptor potential melastatin 8 (TRPM8) channel: A potential new approach for treating dry eye disease

The lacrimal functional unit (LFU) tightly controls the secretion of all tear components, thus playing a critical role in maintaining ocular surface homeostasis. Forming an exquisitely sensitive neural network across the ocular surface, corneal sensory nerves detect environmental stimuli (e.g., temperature, chemicals, and mechanical pressure) through transient receptor potential (TRP) ion channels. Among these, TRP melastatin 8 (TRPM8) is a key regulator of basal tear production. Stimulated by the small temperature reductions and tear film osmolarity increases that arise due to evaporative cooling, TRPM8 activates the LFU, leading to increased basal tear production. Here, we focus on reviewing the topical ocular pathways within the LFU that regulate tear production. We describe the neural signaling underlying this regulation, with a focus on TRP channels and the central role of TRPM8 in basal tear production as elucidated through preclinical as well as limited clinical evidence. Lastly, we explore how augmenting the fundamental action of TRPM8 signaling through agonist stimulation may serve as a valuable new treatment option for dry eye disease.