Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.
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We are grateful to M. W. Panneton, H. Hu, B. Kim, Z. F. Chen, T. P. Margolis and X. Dong for insightful discussions and comments on the manuscript, and we thank A. S. Yoo and Y. Liu for technical support. Mrgpra3GFP-cre, PirtGCaMP3/+ and MRGPRX1;Mrgpr-clusterΔ−/− mice were generous gifts from X. Dong of Johns Hopkins University. MrgprdeGFP/+ mice were from D. J. Anderson of the California Institute of Technology. Trpm8GFP/+ mice were from G. Story. Nav1.8cre, Nmb−/−, Nmbr−/− and NmbrGFP transgenic mice were from Z. -F. Chen of Washington University in St. Louis. Slc17a8Cre/+ tissues were from Q. Ma of Dana-Farber Cancer Institute. This work was supported by the “Research to Prevent Blindness” (RPB) unrestricted grant to the Department of Ophthalmology (A.J.W.H. and Q.L.), and the National Institutes of Health (R01EY024704 and 1R01AI125743; Q.L.) and the Pew Scholar Award (Q.L.).
The authors declare no competing interests.
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Huang, CC., Yang, W., Guo, C. et al. Anatomical and functional dichotomy of ocular itch and pain. Nat Med 24, 1268–1276 (2018). https://doi.org/10.1038/s41591-018-0083-x
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