It has long been established that histamine plays a role as a mediator of inflammation. From numerous studies, it has been well known that the amine has many pharmacological actions on a variety of organs. To evaluate the role of histamine in pain perception, we generated HDC knockout mice using a gene targeting method. Histamine is a hydrophilic autacoid, and in most tissues it is stored and synthesized by mast cells, basophils, parietal cells endothelial cells and neurons. In these deficient mice, the number of mast cells and histamine contents are dramatically decreased. The effects of deletion of histidine decarboxylase on orexin A-induced antinociception were examined on various assays for thermal nociception (tail-flick), mechanical nociception (tail-pressure) and chemical nociception (capsaicin tests) using HDC knockout and their wild-type mice. In these nociceptive assays, intracerebroventricularly (ICV)- administered morphine produced significant anti-nociceptive effects in wild-type mice. The anti-nociceptive effects produced by ICV- administered orexin A were enhanced in HDC knockout mice. These results indicate that antinociception by orexin A was enhanced by decrease in histamine contents. Furthermore, our report demonstrated the possible interactions of orexin A with histaminergic neurons in pain perception, which provides theoretical support for the use of histamine receptor antagonists and orexin A as analgesics in the pain study.