title: Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons.
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.
authors.affiliation: FM Kirby Neurobiology Center and Department of Neurology, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Roberson
authors.forename: Sagi
authors.initials: S
authors.lastname: Gudes
authors.forename: Jared M
authors.initials: JM
authors.lastname: Sprague
authors.forename: Haley A W
authors.initials: HA
authors.lastname: Patoski
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Robson
authors.forename: Felix
authors.initials: F
authors.lastname: Blasl
authors.forename: Bo
authors.initials: B
authors.lastname: Duan
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Bean
authors.forename: Qiufu
authors.initials: Q
authors.lastname: Ma
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Binshtok
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000982:Antipruritics / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D006632:Histamine / Q000633:toxicity; D017442:Histamine Agonists / Q000633:toxicity; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D011537:Pruritus / Q000139:chemically induced / Q000145:classification / Q000188:drug therapy / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000145:classification* / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: D000779:Anesthetics, Local; D000982:Antipruritics; D018501:Antirheumatic Agents; D017442:Histamine Agonists; D026941:Sodium Channel Blockers; D006632:Histamine