The posterior hypothalamus (PH) is known to reduce nociceptive pain, but the effect of PH stimulation on neuropathic pain is not known. Because neurons containing the neurotransmitter orexin-A are located in the PH in some strains of rat and intrathecal injection of orexin-A produces antinociception in a neuropathic pain model, we hypothesized that orexin-A from neurons in the PH modifies nociception in the spinal cord dorsal horn. To test this hypothesis, the cholinergic agonist carbachol or normal saline was microinjected into the PH of lightly anesthetized female Sprague-Dawley rats with chronic constriction injury (CCI) and foot withdrawal latencies (FWL) were measured. Carbachol-induced PH stimulation produced dose dependent antinociception as shown by significantly increased FWL compared to saline controls. To investigate the role of orexin-A in PH-induced antinociception, the orexin-1 receptor antagonist SB-334867 or dimethyl sulfoxide (DMSO) for control, was given intrathecally following carbachol-induced PH stimulation. SB-334867 decreased FWL compared to DMSO controls. These data are suggestive that stimulating the PH produces antinociception in a neuropathic pain model and that the antinociceptive effect is mediated in part by orexin-1 receptors in the spinal cord dorsal horn.