Innocuous warming enhances peripheral serotonergic itch signaling and evokes enhanced responses in serotonin-responsive dorsal horn neurons in the mouse
Itch is often triggered by warming the skin in patients with itchy dermatitis, but the underlying mechanism is largely unknown. We presently investigated if warming the skin enhances histamine- or serotonin (5-HT)-evoked itch behavior or responses of sensory dorsal root ganglion (DRG) cells, and if responses of superficial dorsal horn neurons to innocuous warming are enhanced by these pruritogens. In a temperature-controlled environmental chamber, mice exhibited greater scratching following intradermal (id) injection of 5-HT, but not histamine, SLIGRL or BAM8-22, when the skin surface temperature was above 36°C. Calcium imaging of DRG cells in a temperature-controlled bath revealed that responses to 5-HT, but not histamine, were significantly greater at a bath temperature of 35°C vs. lower temperatures. Single-unit recordings revealed a subpopulation of superficial dorsal horn neurons responsive to id 5-HT. Of these, 58% responded to innocuous skin warming (37°C) prior to id 5-HT, while 100% responded to warming following id 5-HT. Warming-evoked responses were superimposed on the 5-HT-evoked elevation in firing, and were significantly larger compared to responses pre-5-HT as long as 30 min after the id injection of 5-HT. 5-HT-insensitive units, and units that either did or did not respond to id histamine, did not exhibit any increase in the incidence of warmth sensitivity or in the mean response to warming following id injection of the pruritogen. The results suggest that 5-HT-evoked responses of pruriceptors are enhanced during skin warming, leading to increased firing of 5-HT-sensitive dorsal horn neurons that signal non-histaminergic itch.
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