Histamine Modulation of Acute Nociception Involves Regulation of Nav1.8 in Primary Afferent Neurons in Mice

Aims: To explore the role of histamine in acute pain perception and its possible mechanisms. Methods: Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC-/-) mice and their wild-types. Results: HDC-/- mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with a-fluoromethylhistidine (a-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav1.8 expression in primary afferent neurons was increased both in HDC-/- and in a-FMH-treated wild-type mice. A higher Nav1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC-/- mice. Nav1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. Conclusion: Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.