2022.01.07

Histamine enhances ATP-induced itching and responsiveness to ATP in keratinocytes

Yoshihiro Inami, Miki Fukushima, Toshiaki Kume, Daisuke Uta

Abstract

Mechanical stimulation of cultured keratinocytes and a living epidermis increases intracellular calcium ion concentrations ([Ca²⁺]_i) in stimulated cells. This action propagates a Ca²⁺ wave to neighboring keratinocytes via ATP/P2Y₂ receptors. Recent behavioral, pharmacological studies revealed that exogenous ATP induces itching via P2X₃ receptors in mice. We previously showed that alloknesis occurs when an external stimulus is applied to the skin with increased epidermal histamine in the absence of spontaneous pruritus. Based on these results, we investigated the effects of histamine at a concentration that does not cause itching on ATP-induced itching. The mean number of scratching events induced by the mixture of ATP and histamine increased by 28% over the sum of that induced by histamine alone or ATP alone. A317491, a P2X₃ receptor antagonist, suppressed the mixture-induced scratching more often than the ATP-induced scratching. Next, we examined the ATP-induced [Ca²⁺]_i change before and after histamine stimulation using normal human epidermal keratinocytes. Some cells did not respond to ATP before histamine stimulation but responded to ATP afterward, the phenomenon suppressed by chlorpheniramine maleate. These findings suggest that histamine enhances ATP-induced itching and that a potential mechanism could involve increased responsiveness to ATP in keratinocytes.

Keywords: ATP, Histamine, Keratinocytes, Itch, Calcium