Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain
Abstract
:1. Introduction
2. Cornea Nerve Anatomy, Physiology, and Development
3. Cornea Nociceptor Receptors, Channels, and Neurotransmitters
3.1. Nociceptors and the Cornea
3.2. Cornea Nociceptor Receptors and Channels
3.2.1. TRP Channel Superfamily
3.2.2. Acid-Sensing Ion Channels (ASICs)
3.2.3. Mechanosensing Ion Channels
3.2.4. Coding Channels
3.2.5. Interactions and Distinctions Between Nociceptive Channels
3.2.6. Age- and Sex-Related Variation in Ion Channel Expression and Function
3.3. Corneal Neurotransmitters
4. Corneal Nerve Pathology
4.1. Corneal Nerve Lesions and Inflammation
4.2. Dry Eye Disease
4.3. Refractive Surgery
4.4. Keratitis
4.5. Corneal Nerve Growth and Regeneration
5. Nociceptors, Inflammation, and Sensitization
6. Current FDA-Approved Nociceptor-Related Therapies for Ocular Pain
7. Future Therapies and Targets
7.1. Therapies in Development
7.1.1. TRP-Based Therapeutics
7.1.2. NGF-Based Therapeutics
7.1.3. TrkA-Based Therapeutics
7.1.4. Novel Mu-Receptor Therapeutics
7.1.5. Neurokinin 1 Receptor Antagonist Therapeutics
7.1.6. Dual Enkephalinase Inhibitors (DENKIs)
7.1.7. Nav Channel Inhibitors
7.2. Potential Future Targets
7.2.1. PIRT
7.2.2. ASICs
7.2.3. TRPA1
7.2.4. TRPV4
7.2.5. PIEZO2
7.2.6. K2p K+ Channels: TRESK and TREK1
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ASIC | Acid-Sensing Ion Channel |
ATP | Adenosine Triphosphate |
BCL | Bandage Contact Lens |
BDNF | Brain-derived Neurotrophic Factor |
CCL2 | Chemokine Ligand 2 |
CCL3 | Chemokine Ligand 3 |
CGRP | Calcitonin Gene-related Peptide |
CN | Cranial Nerve |
CNS | Central Nervous System |
COX | Cyclooxygenase |
CX3CR1 | CX3C Motif Chemokine Receptor 1 |
DAG | Diacylglycerol |
DAMGO | [D-Ala2, N-MePhe4, Gly-ol]-enkephalin |
DENKI | Dual Enkephalinase Inhibitor |
DRG | Dorsal Root Ganglion |
EGF | Epidermal Growth Factor |
F6H8 | Perfluorohexyloctane |
FDA | Food and Drug Administration |
FM | Fluorescence Microscopy |
GABA | Gamma-aminobutyric Acid |
GDNF | Glial Cell-derived Neurotrophic Factor |
GsMTx4 | Grammostola Mechanotoxin 4 |
IL | Interleukin |
IVCM | In Vivo Confocal Microscopy |
K2P | Two-pore Domain Potassium Channels |
LASIK | Laser-Assisted In Situ Keratomileusis |
LC | Locus Coeruleus |
LIF | Leukemia Inhibitory Factor |
LINE | Laser In Situ Keratomileusis-induced Neurotrophic Epitheliopathy |
LPS | Lipopolysaccharide |
MAPK | Mitogen-activated Protein Kinase |
MDSC | Myeloid-derived Suppressor Cell |
MOR | Mu Opioid Receptor |
mTORC1 | Mammalian Target of Rapamycin Complex 1 |
NGF | Nerve Growth Factor |
NK1R | Neurokinin-1 Receptor |
NSAID | Non-steroidal Anti-inflammatory Drug |
NT | Neurotrophin |
OCT | Optical Coherence Tomography |
OGF | Opioid Growth Factor |
P2 | ATP Receptors |
PACAP | Pituitary Adenylate Cyclase-activating Peptide |
PGE2 | Prostaglandin E2 |
PI3K | Phosphoinositide 3-Kinase |
PIEZO2 | Piezo Type Mechanosensitive Ion Channel Component 2 |
PIP2 | Phosphatidylinositol 4,5-bisphosphate |
PIRT | Phosphoinositide Interacting Regulator |
PNS | Peripheral Nervous System |
PRK | Photorefractive Keratectomy |
PROSE | Prosthetic Replacement of the Ocular Surface Ecosystem |
RNA | Ribonucleic Acid |
ROBO | Transmembrane Roundabout |
RVM | Rostral Ventromedial Medulla |
SAF312 | Libvatrep |
SMILE | Small Incision Lenticule Extraction |
SP | Substance P |
SPRY2 | Sprouty RTK Signaling Antagonist 2 |
T3 | Triiodothyronine |
TASK | TWIK-related Acid-sensitive Potassium Channel 1 |
TGF | Transforming Growth Factor |
TMEM120A | Transmembrane Protein 120A |
TNF | Tumor Necrosis Factor |
TREK | TWIK-related K+ Channel |
TRESK | TWIK-related Spinal Cord K+ Channel |
TrkA | Tropomyosin Receptor Kinase A |
TRP | Transient Receptor Potential |
TRPA | Transient Receptor Potential Ankyrin |
TRPC | Transient Receptor Potential Canonical |
TRPM | Transient Receptor Potential Subfamily M |
TRPP | Transient Receptor Potential Polycystic |
TRPV | Transient Receptor Potential Vanilloid |
TWIK | Tandem of P Domains in a Weak Inward Rectifying K+ Channel |
VEGF | Vascular Endothelial Growth Factor |
YFP | Yellow Fluorescent Protein |
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Associated Corneal Nerve Type | Neurotransmitter |
---|---|
Sensory nerves | Substance P (SP) |
Calcitonin gene-related peptide (CGRP) | |
Pituitary adenylate cyclase-activating peptide (PACAP) | |
Galanin | |
Excitatory amino acids (glutamate, aspartate) | |
Sympathetic nerves | Norepinephrine |
Neuropeptide Y | |
Serotonin (5-HT) | |
Parasympathetic nerves | Vasoactive inhibitory peptide |
Met-enkephalin | |
Neuropeptide Y | |
Galanin | |
Acetylcholine | |
Undetermined | Cholecystokinin |
Brain natriuretic peptide | |
Vasopressin | |
Neurotensin | |
B-endorphin |
Type | Therapeutic | Mechanism | Effect |
---|---|---|---|
Broad-acting | NSAID | COX inhibitor reduces PGE2 release | Decreases nerve sensitization in PNS and CNS |
Acetaminophen | CNS | Decreases nerve sensitization | |
Specific | Bandage contact lenses | Direct physical barrier against mechanical irritants | Increases corneal healing and prevents chronic nociceptive pain |
Perfluorohexyl-octane (F6H8) | TRPM8 activator | Decreases nociceptive pain by improving dry eye symptoms; increases tear production and blinking rate | |
Optive Plus artificial tears | TRPV1 antagonist containing L-carnitine | Decreases pain after 4 weeks |
Stage | Therapeutic | Mechanism | Effect |
---|---|---|---|
Clinical trial—phase 2 | Anti-TrkA monoclonal antibodies | TrkA inhibitor | Decreases nociceptive pain and inflammation |
Dual enkephalinase inhibitors | Inhibit enkephalin degradation, increasing opioid receptor binding | Reduces pain and inflammation | |
Pre-clinical | TrkA inhibitor | Monoclonal antibodies binding TrkA | Decreases nociceptive pain and sensitization in PNS and CNS |
SAF312, TRPV1 antagonist | TRPV1 selective, non-competitive antagonist, Ca2+ influx inhibitor | Inhibits Ca2+ influx into nociceptor cells, decreases inflammation | |
Joint treatment with L-carnitine and capsazepine | TRPV1 antagonist, Ca2+ influx inhibitor | Reduces pain and discomfort | |
Capsazepine, TRPV1, TRPV4, TRPM8 antagonist | Inhibits SP expression; Ca2+ influx inhibitor. | Inhibits Ca2+ influx into nociceptor cells, decreases corneal sensitization and inflammation | |
TRPM8 ion channel antagonist | TRPM8 antagonist | Reduces inflammation | |
DAMGO | Mu opioid receptor (MOR) ligand | Reduces responsiveness of nociceptors | |
Aprepitant | Neurokinin 1 receptor (NK1R) antagonist | Decreases pain sensitivity and BDNF upregulation | |
PIRT | Positive regulator of TRPV1 activity in nociceptive neurons | Influences pain perception, inflammation, and immune response; enhances nerve regeneration | |
NGF | Promotes epithelial migration and proliferation | Improves would healing and nociceptor sensitivity | |
Thy-1 YFP-positive myeloid-derived suppressor cells (MDSCs) | Producers of nerve growth factor (NGF) | Induces nociceptor growth | |
Opioid growth factors | Analgesic | Supports wound healing and nociceptive sensitization |
Channel | Role in Nerve Recovery | Model | Source |
---|---|---|---|
TRPV4 | Ablation of TRPV4 after nerve injury is related to the delay of nerve functional recovery | Mouse cell culture | [1] |
TRPA1 | Blocking TRPA1 results in decreased neuropathic pain in rat models | Rat | [3] |
ASIC3 | ASIC3 might improve tissue repair via a change in the M1: M2 macrophage ratio | Mouse | [4] |
TRESK/TREK1 | Overexpression of TRESK leads to faster mice paralysis recovery and lower TNF-α in blood | Mouse | [5] |
PIEZO2 | PIEZO2 is associated with mechanical allodynia after nerve injury | Mouse, human | [2,6] |
PIRT | PIRT regulates TRPV1 with potential for nerve regeneration | Mouse | [7,8] |
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Park, R.; Spritz, S.; Zeng, A.Y.; Erukulla, R.; Zavala, D.; Merchant, T.; Gascon, A.; Jung, R.; Bigit, B.; Azar, D.T.; et al. Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain. Int. J. Mol. Sci. 2025, 26, 4663. https://doi.org/10.3390/ijms26104663
Park R, Spritz S, Zeng AY, Erukulla R, Zavala D, Merchant T, Gascon A, Jung R, Bigit B, Azar DT, et al. Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain. International Journal of Molecular Sciences. 2025; 26(10):4663. https://doi.org/10.3390/ijms26104663
Chicago/Turabian StylePark, Ryan, Samantha Spritz, Anne Y. Zeng, Rohith Erukulla, Deneb Zavala, Tasha Merchant, Andres Gascon, Rebecca Jung, Bianca Bigit, Dimitri T. Azar, and et al. 2025. "Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain" International Journal of Molecular Sciences 26, no. 10: 4663. https://doi.org/10.3390/ijms26104663
APA StylePark, R., Spritz, S., Zeng, A. Y., Erukulla, R., Zavala, D., Merchant, T., Gascon, A., Jung, R., Bigit, B., Azar, D. T., Chang, J.-H., Jalilian, E., Djalilian, A. R., Guaiquil, V. H., & Rosenblatt, M. I. (2025). Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain. International Journal of Molecular Sciences, 26(10), 4663. https://doi.org/10.3390/ijms26104663