Blocking substance P receptor reduces corneal pain and promotes nerve regeneration after eye injury | Research

The takeaway

NK-1R antagonism with L-733,060 reduced corneal substance P, increased nerve fiber density, decreased neuronal activation markers, and lowered pain perception over 21 days post-corneal injury in mice.

Pain reduced + nerves regenerated
NK-1R antagonism simultaneously reduced corneal pain AND improved nerve fiber regeneration—a dual-benefit approach not available with current eye pain treatments

What the researchers found

NK-1R antagonist (L-733,060): ↓corneal SP, ↑nerve fiber density at 21 days, ↓trigeminal activation markers (ATF3, GFAP, cFos, TRPV1, TRPM8), ↓pain responses (eye-wiping test + palpebral ratio). 21-day topical treatment.

Why it matters

Corneal pain after injury or surgery is debilitating. NK-1R antagonists could simultaneously reduce pain and promote nerve healing—unlike current analgesics that only address symptoms.

How the study worked

C57BL/6 mice corneal injury model. L-733,060 or vehicle topical 2x daily for 21 days. ELISA (SP), β-Tubulin III staining (nerve density), qPCR (trigeminal markers), pain behavioral tests (EWT, PR).

What this study cannot tell us

Mouse model. Topical delivery of L-733,060 (not a clinically available eye drop). 21-day study may not capture long-term effects. Pain assessment in mice has limitations.

How to read the evidence

Well-designed preclinical study with behavioral, molecular, and histological endpoints. Strong mechanistic evidence.

When this study was published

Published in 2025.

The bigger picture

Substance P antagonism for ocular pain addresses both sensory and regenerative aspects of corneal injury—a dual-benefit approach not available with current treatments. NK-1R antagonists (like aprepitant) are already approved for other indications.

Questions still open

Could aprepitant (approved NK-1R antagonist) be formulated as eye drops?
Would SP antagonism benefit post-LASIK corneal nerve pain?
Does improved nerve regeneration with NK-1R blockade translate to better corneal sensitivity?

Common questions

How does substance P cause eye pain?

After corneal injury, substance P accumulates in the cornea and activates NK-1 receptors, causing pain, inflammation, and neuronal hyperactivation. Blocking these receptors with an antagonist not only reduced pain but also unexpectedly improved nerve regeneration—suggesting substance P actually impairs healing.

Could this lead to better eye pain treatment?

Yes. Current eye pain treatments are limited to numbing drops and NSAIDs, which do not promote healing. NK-1R antagonist eye drops could reduce pain while actively supporting nerve regeneration—a significant improvement for patients recovering from corneal surgery or injury.

Read the original research

Antagonizing NK-1R modulates pain perception following corneal injury.

Experimental eye research, 251, 110230

View on PubMed ↗Publisher’s paper ↗

Citation

Surico, Pier Luigi; Naderi, Amirreza; Singh, Rohan Bir; Kahale, Francesca; Farsi, Yeganeh; Lee, Seokjoo; Musayeva, Aytan; Chen, Yihe; Dana, Reza. (2025). Antagonizing NK-1R modulates pain perception following corneal injury.. Experimental eye research, 251, 110230. https://doi.org/10.1016/j.exer.2025.110230