Topical Blockade of Substance P May Relieve and Prevent Allergy-Related Redness

Topical application of an SP-blocking agent decreases histamine-caused ocular redness.

A topical application of substance P (SP) can potentially relieve and prevent allergy-related ocular redness, according to results of a study published in Ocular Surface.

“Recent insights into the mechanisms of SP-induced neurogenic vasodilation have provided a new therapeutic target for the  treatment of conjunctival hyperemia,” the study authors explain.

SP, an amino acid tachykinin expressed in the central and peripheral nervous systems, is secreted by sensory nerve endings, including corneal trigeminal nerves and corneal epithelial cells. The biological actions of SP are primarily mediated through the neurokinin-1 receptor (NK1R), which is expressed by various types of cells, including mast cells.

The study, conducted at Harvard Medical School, included male Dunkan-Hartley guinea pigs that had induced ocular redness using 20 μL of 1.5 mg/mL histamine. After induction, ocular redness was assessed by slit lamp imaging every 30 seconds for 2 minutes, followed by every 4 minutes for 8 minutes, and every 10 minutes for 1 hour. Images were scored using the ocular redness index (ORI) by 2 blinded investigators. Some animals were treated with 20 μL non-peptide NK1R antagonist L-703,606 in a concentration of 1mg/mL 10 minutes before or after histamine induction. In addition, SP was evaluated in 20 μL of tears. After euthanization, eyeballs were stained and eosinophils and neutrophils in the blepharal and bulbar conjunctiva counted.

Recent insights into the mechanisms of SP-induced neurogenic vasodilation have provided a new therapeutic target for the  treatment of conjunctival hyperemia.

At 30 seconds after histamine induction, ORI increased by 11.70±0.70 from baseline and peaked at 10 minutes to a maximum score of 17.04±0.99.

The application of L-703,606 10 minutes prior to histamine decreased ORI by 50% at all timepoints compared with controls. Applying L-703,606 10 minutes following histamine induction resulted in a more than 30% reduction in ORI scores within 20 minutes of application compared with controls. Efficacy of L-703,606 was observed until the end of the observation period.

Conjunctival blood vessel diameters of histamine-treated animals were an average of 30.66 μm compared with 10.15 μm observed in control animals. Pretreatment with L-703,606 decreased blood vessel diameters to 16.84 μm prior to histamine induction and 23.69 μm following histamine aggravation.

Histamine application increased mast cells from baseline (mean 87.5 vs 245.9 mm2), eosinophils (mean, 31.67 vs 176.3 mm2), and neutrophils (mean, 24.33 vs 126.3 mm2), respectively. Pre-induction treatment with L-703,606 decreased all inflammatory cell infiltration by 50% and by 30% for post-induction treatment.

The tears from animals with allergy-induced ocular redness showed increased SP compared with controls (mean, 270.6 vs 71.64 pg/mL), respectively, with significantly decreased SP levels after pre-induction (mean, 154.1 pg/mL) and postinduction (mean, 191.1 pg/mL) treatment.

The major limitation of this study was the use of an animal model. These findings should be confirmed among humans.

Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Wang S, Liu L, Blanco T, et al. Therapeutic efficacy of topical blockade of substance P in experimental allergic red eye. Ocul Surf. 2022;26:184-190. doi:10.1016/j.jtos.2022.08.008