Abstract
The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1+ or TRPA1+ neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus.
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Acknowledgements
We thank N. Ghasemlou and S. Ross for discussion and O. Viramontes for technical assistance. This study was supported by the US National Institutes of Health (NS072040 to B.P.B., Q.M., B.D. and C.J.W.; NS047710 to B.D. and Q.M.). J.M.S. is a recipient of a Ruth L Kirschstein National Research Service Award from the National Institute of Dental and Craniofacial Research.
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D.P.R. conceived, designed and conducted the behavioral experiments, analyzed behavioral data, and wrote the manuscript. S.G. performed the combined calcium-imaging and electrophysiology experiments. J.M.S. carried out the calcium-imaging experiments. H.A.W.P. and V.K.R. conducted behavioral experiments and analyzed behavioral data. F.B. contributed to the combined calcium-imaging and electrophysiology experiments. B.D. contributed to behavioral experiments and interpretation of behavioral data. S.B.O. gathered behavioral pilot data and gave manuscript advice. B.P.B. conceived the silencing strategy, gave technical and conceptual advice, and edited the manuscript. Q.M. provided critical analysis and interpretation of behavioral data, designed behavioral experiments, and contributed to critical revision of the manuscript. A.M.B. conceived the silencing strategy, conceived and designed behavioral experiments and the combined calcium-imaging and electrophysiology experiments, gathered behavioral pilot data, supervised the project, and wrote the manuscript. C.J.W. conceived the silencing strategy, supervised the project and wrote the manuscript.
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This research was funded, in part, by a research grant from Endo Pharmaceuticals, who have licensed the technology invented by B.P.B. and C.J.W
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Roberson, D., Gudes, S., Sprague, J. et al. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat Neurosci 16, 910–918 (2013). https://doi.org/10.1038/nn.3404
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DOI: https://doi.org/10.1038/nn.3404
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