Repetitive administration of opioid agonists rapidly develops tolerance to the effects of these substances and limits their application. Orexin is involved in morphine tolerance and withdrawal. The Lateral Paragigantocellularis (LPGi) is a key brain region implicated in the tolerance and dependence to opiates. In the current study, the effect of OXR1 blockade on tolerance to antinociceptive effect of morphine and also on the neural activity of LPGi during the development of morphine tolerance was studied. Male Wistar rats weighing 250-300g were used in these studies. To incite tolerance, morphine sulfate was injected intraperitonealy (10mg/kg, i.p.) once a day for 7 days. Tail flick test was used to survey morphine analgesic tolerance. A selective orexin type 1 receptor antagonist (SB-334867) was microinjected into the right cerebral ventricle (10μg/10μl, i.c.v.) immediately before morphine injection. To evaluate tolerance at the cellular level, On day 7 the effect of morphine (10mg/kg, i.p.) on neural activity of LPGi was investigated using in vivo extracellular single unit recording. In the behavioral studies, daily injections of morphine in a 7-day period caused morphine analgesic tolerance in rats. There was a significant difference of %MPE between saline and morphine treated rats until day 6 but not on day 7 (Data was presented as mean±SEM. *P < 0.05, **P < 0.01 and ***P < 0.001 vs. saline group, n = 6 for both groups; one-way ANOVA followed by Tukey’s post test). The analgesic effects of morphine (%MPEs) were significantly higher in SB-334867 plus morphine treated rats (n=9) than SB vehicle plus morphine treated (n=11) ones on days 4-7 (Data was presented as mean±SEM. *P < 0.05, **P < 0.01 and ***P < 0.001 vehicle plus morphine, one-way ANOVA followed by Tukey’s post test). In the electrophysiological studies, 6 days injection of morphine caused significant tolerance in LPGi neurons as a decreased responsiveness of neurons to morphine (10 mg/kg, i.p.) during single unit recording. In a way that on day 7 morphine has not created any significant change in the firing rate of LPGi nucleus. (Data was presented as mean±SEM, n=10; Student’s paired t-test). In SB plus morphine treated group (n=17), Microinjection of SB before each morphine injection inhibited the development of tolerance to morphine in comparison to the morphine treated group (Data was presented as mean±SEM, Student’s paired t-test). These studies have shown that central blockade of orexin type 1 receptor inhibits the development of morphine tolerance in both studies. The impediment of tolerance to analgesic effect of morphine by ICV administration of orexin type 1 receptor antagonist may be mediated in part via LPGi neurons. Further studies are required to determine molecular and anatomical mediators which are thought to be involved in this phenomenon.