A multi-species model for selective pruritus via the direct activation of TRPA1

Abstract

Pruritus, or itch, is an unpleasant cutaneous sensation that elicits a desire to scratch. In mammals, this sensation occurs when itch-inducing stimuli activate pruritic receptor proteins on somatosensory neurons, which functionally couple to transient receptor potential (TRP) ion channels to elicit neuronal activation. However, little is known about the capacity of lower vertebrates to experience itch, or the potential neuronal mechanisms that might underlie this sensation. To address this gap in knowledge, we used a variety of experimental methods to determine whether itch existed in a lower vertebrate, the zebrafish (Danio rerio). We confirmed that zebrafish are indeed capable of uniquely pruritic behavioral responses to itch stimuli that are distinct from nocifensive (pain) responses. Unlike previously-described itch transduction mechanisms in mammals, these pruritic responses resulted from the direct activation of the TRP ion channel TRPA1 on a selective subset of somatosensory neurons that were primed to respond to lower-intensity noxious stimuli like pruritogens. Higher-intensity stimuli that elicited nocifensive behaviors instead activated additional subpopulations of less-sensitive, higher-threshold TRPA1 neurons. This suggests that distinct populations of differentially-tuned TRPA1 neurons can be activated to relay either itch or pain. Intriguingly, this mechanism was also present in the mouse, implying that this form of itch transduction is perhaps a rudimentary, evolutionarily early form of itch that persisted, and was later expanded upon, in terrestrial vertebrates. Additional experiments provided anatomical evidence that multiple subpopulations of TRPA1 neurons exist in both the mouse and the zebrafish, and found that PLC activity may play a role in setting the gain of the more sensitive neurons. Together, these results suggest a multi-species model for selective itch via the activation of a specialized subpopulation of somatosensory neurons with a heightened sensitivity to noxious stimuli.