Changes Of Na_v1.8 In Primary Afferent Neurons And Hypersensitive Nociception In Histidine Decarboxylase Knock-out Mice

To understand the effect of histamine on voltage-gated sodium channel subtype 1.8 (Nav1.8) and pain perception, we studied Nav1.8 expression and characteristics in nociceptive primary afferent neurons of dorsal root ganglion (DRG) and excitability of these neurons in histidine decarboxylase knockout mice (HDC-/-, lack of endogenous histamine) as well as the nociceptive sensitivity of these mice. The expression of Nav1.8 in nociception related small DRG neurons from HDC-/- mice were upregulated and the current intensity of Nav1.8 in these neurons was also higher. Moreover, the voltage-dependence of Nav1.8 activation and inactivation were shifted in the hyperpolarizing direction in mutated mice. In addition, the injection current required to evoke action potentials was significant lower for neurons in HDC-/- mice, and the firing rate in response to a suprathreshold stimulation was higher than that in HDC+/+ mice. Repeated treatment with a-fluoromethylhistidine (a-FMH, an inhibitor of HDC) on HDC+/+ mice upregulated the expression of Nav1.8 in nociceptive DRG neurons. Behavioral tests revealed that nociceptive thresholds for acute thermal (hot-plate), mechanical (tail-pressure) and chemical (acetic acid, formalin) stimulation were lower in HDC-/- mice compared with wild-types. Either repeated or once systemic a-FMH treatment yielded pronociception in HDC+/+ mice, while intracerebroventricular administration of histamine inhibited thermal nociception in HDC-/- mice. Our results indicated that depletion of endogenous histamine upregulates expression and activities of Nav1.8, which may contribute to the hyperexcitability of nociceptive primary afferent neurons. These changes may underlie the enhanced nociceptive sensitivity of HDC-/- mice.