Orexins are produced from neurons which are restricted to a few regions of the lateral hypothalamus (LH), where they are important in pain modulation. The orexin receptors and orexinergic projections are localized in regions previously shown to play a role in pain modulation such as rostral ventromedial medulla (RVM). The effect of orexin-A (ORXA) microinjection into the RVM on nociceptive behaviors was examined using the formalin test. Microinjection of ORXA into the RVM, but not adjacent reticularis gigantocellularis (Gi) nucleus, decreased formalin induced nociceptive behaviors. Pretreatment with a selective OX1R antagonist, SB-334867 inhibited the antinociception produced by ORXA, while the administration of SB-334867 alone had no effect. These data demonstrate that ORXA-induced antinociception in the formalin test is mediated in part through orexin1 receptors in the RVM.