TRP’n Out: OSD, Inflammation, and Nerves
Patients with dry eye disease (DED), ocular surface disease (OSD), and other cornea and anterior segment diseases experience a diverse spectrum of symptoms, from debilitating pain to a pathologic lack of symptoms, as seen in neurotrophic diseases.1,2 Understanding why and how these symptoms present, their interactions with ocular healing, and the dysfunctions that occur in this process can make us better doctors and help us care for our patients.
The cornea is the most densely innervated tissue and the most powerful pain generator in the human body. In fact, this tissue has 40-fold greater nerve density than the mouth and 100-fold greater nerve density than our skin.3 Additionally, the cornea possesses the highest density of nerve endings in the body, estimated at 16,000 nerve terminations/mm, making it—and the neurologic processes surrounding cornea and anterior segment diseases—a logical target for therapeutics and research.3,4
A renewed focus on inflammation and the inflammatory response of the ocular surface has greatly increased our understanding of these pathologies. As a result, more specific and selective antiinflammatory therapeutics have entered the scene, expanding our treatment arsenal. This article introduces some basic neurogenic considerations and processes, which will hopefully inspire you to explore these topics further on your own.
THE NERVE ENDING IS THE BEGINNING: AN INTRO TO TRPs
Maintenance of corneal health requires monitoring and feedback from the extensive network of nerve nociceptors, or nerve endings. There are several types of nociceptors, including chemical, thermoreceptor, mechanical, and polymodal.3-5 Their sensory responses to various stimulating forces are linked to the specific expression of transient receptor potential (TRP) channels, which are a superfamily of signaling channels. The TRP family is comprised of more than 50 channels that play roles in signaling physiological processes.3 TRP channels are responsive to many exogenous and endogenous biomolecules that can lead to disease pathophysiology, such as physical injury (eg, corneal abrasion), chemical injury (eg, capsaicin or pepper spray), or change in temperature (eg, cold air, cooling effects from evaporation, or thermal burns).3
Many TRPs are expressed in the eye on both neuronal and non-neuronal cells, where they affect numerous regulatory responses that are essential for normal tissue function and maintenance.3-5 There are too many TRPs to comprehensively review here, but I will mention a few that are attracting attention in eye research.
WHAT YOU NEED TO KNOW ABOUT TRPs
TRP melastatin member 8 (TRPM8) is a cold-sensing receptor found on nerve endings of the ophthalmic branch of the trigeminal nerve.3 TRPM8 channels sense cooling changes in corneal temperature, such as those associated with tear evaporation.3 TRPM8 receptors have been associated with tear production by detecting ocular surface dryness and are activated by evaporative cooling and hyperosmolarity, leading to stimulation of tear production, which may be why eyes water on cold days and in patients with dry eye.3-5
In one study, TRPM8 knockout mice demonstrated reduced basal tearing and a decreased cold response.3 Agonists of TRPM8 promote a cooling sensation that may be beneficial for reducing ocular discomfort and pain.3-5 This phenomenon may be related to some of the reduced pain seen by Epitropoulos et al, with improved comfort of therapeutics by instilling Rohto Dry Aid Eye Drops for Dry Eye (Rohto Eye Drops) and its menthol TRPM8 stimulator before instillation of dry eye therapeutics.6
AR-15512 (Aerie/Alcon), a TRPM8 agonist, is being evaluated for its potential dual role in the treatment of DED by both stimulating tear production and reducing ocular discomfort.4 TRPM8 has also been shown to be a pharmacologic target of tacrolimus, which is a common therapeutic used in cornea and ocular surface clinics. Tacrolimus is also prescribed to prevent organ rejection and to treat atopic dermatitis.3 Because the activation of TRPM8 can prevent other abnormal nociceptive inputs, agents for targeting this channel may have the potential to relieve neuropathic eye pain, a major symptom behind some of the most challenging cases clinicians who treat OSD encounter.2
It should be noted that there is some debate in the literature regarding the agonist versus antagonist of TRPM8 in OSD. Some studies consider TRPM8 agonists to be an effective treatment for DED, while others suggest that TRPM8 antagonists could relieve DED.3
ALDEHYDES AND OXIDATIVE STRESS
As mentioned above, inflammation and the response to inflammatory mediators plays a large role in the fight against OSD. As we have learned more about inflammation, our research has focused more on the early signals of stress or injury because, as we all now know, earlier intervention is better.
Reactive aldehyde species (RASP) are produced during oxidative stress and have been found at elevated levels in both acute and chronic disease states.5 Recent research has also shown that RASPs trigger changes in TRP channels, inducing proinflammatory cascades.5
Aldeyra Therapeutics’ New Drug Application for topical reproxalap, an investigational new drug candidate for the treatment of signs and symptoms of DED, was accepted by the FDA in November.7 There is some evidence that the RASP inhibitor may have therapeutic effects in not only OSD, but also allergic conjunctivitis and even uveitis, possibly revealing a broad therapeutic implication in eye care.8
THE QUEST GOES ON
The continued exploration of OSD processes will reveal a more complete understanding of these intricate and multifactorial conditions. TRP channels and a more thorough knowledge of inflammatory cascades push us forward. However, some controversies persist, and much work remains regarding the pharmacologic use of TRP agonists and antagonists in ocular disease states.
As our understanding expands and therapeutics become more specific and targeted, we can look forward to helping more individuals with this underaddressed and undertreated condition.
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