The Itching Line. Selective Silencing of Primary Afferents Reveals Two Distinct Itch-Specific Sensory Lines

Histamine-dependent and histamine-independent itch are detected and transduced in primary sensory neurons through distinct molecular signaling mechanisms. It remains unclear, however, whether pruritogens activate these mechanisms within the same or different afferents and if these afferents are dispensable for pain. To address this, we have selectively blocked histamine-dependent and -independent primary afferent fibers in vivo using targeted delivery of the membrane-impermeant sodium-channel blocker, QX-314. Silencing histamine-sensitive pruriceptors abolished subsequent histamine-evoked scratching but not that produced by the histamine-independent pruritogens chloroquine and SLIGRL-NH₂, and vice versa. We conclude that distinct fibers mediate the two itches. Moreover, we also demonstrate that targeted blockade of itch does not reduce pain-associated behavior, implying that pruriceptors are a labeled line only for itch.