OBJECTIVE To explore the role of histamine in a cute pain perception.METHODS We studied the sensitivity to acute pain in histidine decarboxylase knockout mice (HDC-/-), wild-type mice treated with o-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, and mice feed a low-hista mine diet.Morphological, Western blotting and Electrophysiolo gy studies were taken to explore the involvement of sodium chan nel 1.8 (Nay 1.8) in the pathological process.RESULTS Behavioral tests revealed that HDC-/-mice had lower nocicep tire thresholds for acute thermal (hot-plate), mechanical (tailpressure) and chemical (acetic acid and formalin) stimulation than the wild-type.The low-histamine diet elevated the sensitivi ty to all these noxious stimuli in the wild-type, and to heat and formalin stimuli in the HDC-/-mice.α-FMH treatment also augmented acute thermal nociception in the wild-type.Morpho logical and Western blotting studies showed that both HDC knockout and ot-FMH treatment increased the expression of Nav1.8 in nociceptive primary afferent neurons.The higher Nay1.8 current density in nociception-related small DRG neu rons of HDC-/-mice verified this upregulation.Moreover, the current required to evoke action potentials was significantly low er, and the firing rate in response to suprathreshold stimulation was higher in neurons from HDC-/-mice.The hyperexcitability of DRG neurons in HDC-/-mice was diminished by a Nav1.8inhibitor, but not TTX.CONCLUSION Our results indicate that histamine participates in acute pain modulation, which may be related to the regulation of Nav1.8 in, as well as the excita bility of, nociceptive primary afferent neurons.