Abstract
Little is known about the capacity of lower vertebrates to experience itch. A screen of itch-inducing compounds (pruritogens) in zebrafish larvae yielded a single pruritogen, the TLR7 agonist imiquimod, that elicited a somatosensory neuron response. Imiquimod induced itch-like behaviors in zebrafish distinct from those induced by the noxious TRPA1 agonist, allyl isothiocyanate. In the zebrafish, imiquimod-evoked somatosensory neuronal responses and behaviors were entirely dependent upon TRPA1, while in the mouse TRPA1 was required for the direct activation of somatosensory neurons and partially responsible for behaviors elicited by this pruritogen. Imiquimod was found to be a direct but weak TRPA1 agonist that activated a subset of TRPA1 expressing neurons. Imiquimod-responsive TRPA1 expressing neurons were significantly more sensitive to noxious stimuli than other TRPA1 expressing neurons. Together, these results suggest a model for selective itch via activation of a specialized subpopulation of somatosensory neurons with a heightened sensitivity to noxious stimuli.
Highlights
Itch is an unpleasant sensation that elicits a scratch behavior in terrestrial vertebrates
In contrast to previous reports, we found no evidence that TLR7 coupled with TRPA1 in the presence of loxoribine as measured by ratiometric calcium imaging and whole cell electrophysiology in mouse and zebrafish (Figure 3—figure supplement 2A–D) (Liu et al, 2010)
We found that both IMQ and Allyl isothiocyanate (AITC) responses were completely abolished in dorsal root ganglion (DRG) neurons obtained from Trpa1-/- animals, while neurons from WT siblings exhibited normal responsivity to both stimuli (Figure 5B,C)
Summary
Itch is an unpleasant sensation that elicits a scratch behavior in terrestrial vertebrates. Chemically-induced itch is thought to be mediated by pruritic receptors on somatosensory neurons (Bautista et al, 2014; Hoon, 2015) These receptors are typically G-protein coupled receptors (GPCRs) that, upon activation, prompt the opening of downstream transient receptor potential (TRP) channels, facilitating activation of the neuron (Ross, 2011; Zhang, 2015). This coupling of pruritic receptors to TRPA1 or TRPV1 is especially intriguing in that these TRP channels serve as nociceptors, mediating responses to algogenic (painful) stimuli (Laing and Dhaka, 2016; Ikoma et al, 2006). Studying how these itch genes operate in the somatosensory system of zebrafish could reveal conserved itch transduction mechanisms, providing insight into the evolution of itch
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