Orexins (hypocretins) are novel peptides that have been shown to play a role in control of behavioral arousal. The paraventricular nucleus of the midline thalamus (PVT) is one area of the brain that is the most densely innervated by orexin fibers. In addition, the PVT sends a dense projection to the nucleus accumbens, an area of the striatum involved in the regulation of locomotion. This study was done to determine the effect of microinjections of orexin-A (OXA) or the orexin receptor antagonist SB334867 in the PVT on locomotor activity (LA) in morphine-naïve and morphine-sensitized rats. Microinjections of OXA (3 microg/500 nl) in or near the PVT inhibited LA in rats tested in a novel and familiar environment as well as in rats expressing behavioral sensitization to repeated injections of morphine. In contrast, microinjections of SB334867 had no effect on LA in any of the test situations. Using an approach involving experimenter based analysis of ethological behaviors; we found that microinjections of OXA in the midline thalamus decreased LA while at the same time increasing the expression of grooming and freezing. These results suggest that OXA can act on the PVT and the midline thalamus to produce arousal independent of LA.