PROJECT SUMMARY / ABSTRACT The cornea is the most densely innervated tissue of the body, making it vulnerable to various insults and neurosensory abnormalities that can lead to severe pain. Ocular pain is a very common complaint, and yet its available management options remain quite limited. While “pain” in the acute sense has protective usefulness (signaling the host to limit exposure to noxious stimuli), when protracted in the absence of ongoing insult, it can cause persistent tissue damage and induce chronic neuropathic pain. Pathological ocular pain is often persistent, and is associated with low-grade chronic inflammation, as observed in the highly prevalent condition of dry eyes or after corneal injuries (including refractory surgery). We have been actively investigating the neuro-immune crosstalk at the ocular surface, and our studies have demonstrated the critical involvement of the neuropeptide substance P (SP) and its preferred receptor, neurokinin-1 receptor (NK1R), in exacerbating corneal epitheliopathy through inducing neurogenic inflammation in both cornea and trigeminal ganglions (TG) where the primary sensory neurons for cornea are located. The SP/NK1R pathway is well known for mediating nociceptive pain, and its additional functions in inducing neurogenic inflammation further evoke significant long-term genetic and molecular changes that modify the electrophysiological characteristics of the peripheral terminals, parent axons, and cell bodies of the primary sensory neurons, resulting in dysregulated transmission and processing of pain signals thereby leading to chronic pain. Importantly, our preliminary studies have shown that topical NK1R antagonist effectively suppresses acute ocular pain when given immediately after the insults in animals. In the current proposal, we hypothesize that topical NK1R antagonist is a non-addictive analgesic capable of suppressing chronic ocular pain through disrupting SP-mediated both nociceptive pathway and neurogenic inflammation that amplifies the vicious pain cycle. The principal objectives of this project are to (i) assess the analgesic efficacy of NK1R antagonist in ocular pain, and (ii) determine the effects of NK1R antagonist on the ocular surfaceꟷTG neurosensory pathway. To achieve these objectives, two specific aims will be pursued: Aim 1: We will determine whether topical treatment with NK1R antagonist is effective in reducing chronic ocular pain without causing addiction or ocular side effects; and Aim 2: We will assess the effects of NK1R antagonist on modulating cellular and molecular activities within the ocular surfaceꟷTG neurosensory pathway. Results from this study will help to validate a potential target in managing protracted ocular pain, and thus lay a foundation for our next steps toward clinical translation. We will also establish a multi-disciplinary team with the required expertise to prepare for the subsequent application from our team.