A zebrafish and mouse model for selective pruritus via direct activation of TRPA1

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.

Differential contribution of sensory transient receptor potential channels in response to the bioactive lipid sphingosine-1-phosphate

“…(b) Mechanical thresholds for avoidance behaviors to mechanical stimulation of mice 1-h after injection of saline and S1P as in Figure 6 the reports that have recently shown the induction of pain and itch behavior occurring in a dose-dependent manner. 29,73 One study is based on the chemicalinduced activation of pruriceptors and nociceptors in zebrafish and mice. 73 The authors used imiquimod, a weak activator of TRPA1 channel, followed by AITC, a strong activator, and observed this phenomenon of affinity driven activation of the TRPA1 channel.…”

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

“…NGF and its receptor may be one of the treatment targets for itch. 43 Although the serum level of brain-derived neurotrophic factor in patients with CTCL is not higher than normal people, the serum level of NGF is higher than healthy people.…”

“…Imiquimod was a direct but weak TRPA1 agonist and imiquimod-responsive TRPA1 + neurons were more sensitive than other TRPA1 + neurons in response to noxious stimuli. 43…”

Small RNAs, but Sizable Itch: TRPA1 Activation by an Extracellular MicroRNA

“…These findings fit with the observation that AITC, but not miR-711, causes neurogenic inflammation, which occurs in response to Ca 2+ influx into primary afferents, raising the possibility that AITCinduced pain is largely secondary to afferent-induced flare. An alternative possibility is that a weaker TRPA1 stimulus (i.e., miR-711) is only sufficient to activate primary afferents with high TRPA1 expression (putative itch-specific), whereas a stronger TRPA1 stimulus (i.e., AITC) is able to activate a broader population of sensory neurons, thereby occluding itch and causing pain (Esancy et al, 2018). This issue of coding is surprisingly elusive, so for now we will simply have to wait, itching (or aching?)…”