Orexins are neuropeptides that are mostly expressed in the posterior and lateral hypothalamus, and related to the central control of appetite, arousal, and antinociception. Orexin neurons projected to the tuberomammillary nucleus and orexins may release histamine from the histamine neurons in this nucleus. Histamine is known to cause hypernociception. The roles of histamine H1 and H2 receptors in the orexin A-induced antinociception, however, have not been clarified yet. Here we studied the effects of histamine H1 and H2 receptors on orexin A-produced antinociception using histamine receptor knockout mice in four assays of nociception; the hot-plate, the tail-flick, the tail-pressure and the capsaicin tests. Furthermore we studied effects of histamine H1 and H2 receptor antagonists on orexin A-produced antinociception in C57BL/6 mice. The antinociceptive effects of i.c.v. orexin A were greater in histamine H1 receptor or H2 receptor knockout mice than in the wild-type mice in all four assays of pain. Furthermore, treatment of C57BL/6 mice with a combination of i.c.v. orexin A and d-chlorpheniramine (a histamine H1 receptor antagonist) or cimetidine (a histamine H2 receptor antagonist) showed a greater antinociception than i.c.v. orexin A alone in all four assays. These findings suggest the possibility that orexin A may activate H1 and H2 receptors in the supraspinal levels through the release of histamine from neurons, which might attenuate the antinociceptive effects of orexin A. Thus, the blocking of the histamine H1 or H2 receptor may produce antinociception and enhance the orexin A-induced antinociception.