Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice.

Abstract

Itch, a common clinical symptom of many skin diseases, severely impairs the life quality of patients. Nav1.7, a subtype of voltage-gated sodium channels mainly expressed in primary sensory neurons, is responsible for the amplification of threshold currents that trigger action potential (AP) generation. Gain-of-function mutation of Nav1.7 leads to paroxysmal itch, while pharmacological inhibition of Nav1.7 alleviates histamine-dependent itch. However, the crosstalk between histamine and Nav1.7 that leads to itch is unclear. In the present study, we demonstrated that in the dorsal root ganglion (DRG) neurons from histamine-dependent itch model mice induced by compound 48/80, tetrodotoxin-sensitive (TTX-S) but not TTX-resistant Na+ currents were activated at more hyperpolarized membrane potentials compared to those on DRG neurons from vehicle-treated mice. Meanwhile, bath application of histamine shifted the activation voltages of TTX-S Na+ currents to the hyperpolarized direction, increased the AP frequency, and reduced the current threshold required to elicit APs. Further mechanistic studies demonstrated that selective activation of H1 but not H2 and H4 receptors mimicked histamine effect on TTX-S Na+ channels in DRG neurons. The protein kinase C (PKC) inhibitor GO 8963, but not the PKA inhibitor H89, normalized histamine-sensitized TTX-S Na+ channels. We also demonstrated that histamine shifted the activation voltages of Na+ currents to the hyperpolarized direction in Chinese hamster ovary (CHO) cells expressing Nav1.7. Importantly, selective inhibition of Nav1.7 by PF-05089771 significantly relieved the scratching frequency in a histamine-dependent itch model induced by compound 48/80. Taken together, these data suggest that activation of H1 receptors by histamine sensitizes Nav1.7 channels through the PKC pathway in DRG neurons that contributes to histamine-dependent itch.