Concomitant Topical Treatment of Pain and Inflammation in Ocular Injuries
Abstract
Objectives and Rationale of Project: Mechanical and chemical insults to the eye can cause significant damage to the cornea and its dense network of nerves, which are responsible for sensation and play an important role in the blink reflex, wound healing, and tear production. Injury to the cornea is typically intensely painful and the inflammatory response potent, leading to neovascularization and scarring that can affect corneal clarity and thus vision. Substance P (SP) is a nerve-derived molecule that plays important functions. When over-expressed as a result of injury or inflammation, SP can itself lead to significant pain and inflammation. This response is known as neurogenic inflammation since the factors that cause inflammation (such as SP) are secreted by nerves. SP functions through its principal receptor, the neurokinin-1 receptor (NK1R). Our preliminary data, as shown in our application, demonstrate that blocking the signaling of NK1R has a remarkable capacity in reducing not only inflammation but also pain sensation. Based on these preliminary data, our objectives in this grant are to use the mechanical and chemical corneal injury models to evaluate the effect of NK1R antagonism on (i) corneal pain and (ii) inflammation, edema, and scarring. How the Proposal Addresses an Area of High Unmet Need: Currently, there is no safe and effective treatment to treat ocular pain and inflammation. Current therapies for inflammation include topical corticosteroids and nonsteroidal anti-inflammatories, but they have (1) limited efficacy for pain and (2) carry the risk of delayed wound healing and corneal melting. Treatments for ocular pain are even further inadequate: Topical anesthetics are effective only for transient management of pain because of their significant side effects such as toxic keratopathy, corneal melting, and perforation. Oral medications such as NSAIDs and opioids, can also control ocular pain, although their use comes with significant side-effects such as GI disturbance and renal toxicity for NSAIDs and a plethora of complications for opioids including addiction. Based on the published evidence and our extensive preliminary data, we propose that antagonism of neurokinin-1 receptor (NK1R), the principal receptor of Substance P, can be exploited to concomitantly suppress inflammation and pain perception in traumatized eyes. NK1R antagonism is a unique strategy because SP/NK1R signaling is involved in activation of both nociceptive (pain perception) and inflammatory pathways. Therefore, strategies to suppress pain and inflammation concurrently have the potential to truly transform the management of ocular injuries in addition to a myriad of other conditions. How will this Research Advance Ocular Care and Research as it Applies to the Military and Civilian Populations? There is a clear unmet need for effective treatment of corneal inflammation and pain. Such a therapeutic would not only transform the outcomes of ocular injuries among both civilians and Warfighters sustaining ocular injuries but would also hold tremendous promise for pain and inflammation following a variety of intraocular procedures. This proposal also provides insights into the mechanisms that link pain and inflammation in ocular tissue. How will this Research Make Significant Advancements to Clinical Translation? In this 3-year project, we propose a clear line of investigation to (1) determine the efficacy of NK1R antagonism in suppressing pain following mechanical and chemical injury, and to (2) determine the efficacy of NK1R antagonism in suppressing inflammation and scarring following mechanical and chemical injury. These issues have major implications for the ultimate treatment of corneal injuries in both civilian and military populations. The knowledge gained from the proposed line of research will position us well to eventually file for Investigational New Drug approval from the U.S. Food and Drug Admin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210839
Entities
People
- Reza Dana
Organizations
- Schepens Eye Research Institute
- United States Army