AbstractPurposeThe interaction of orexinergic neurons with the opioidergic system and their effects on morphine analgesia and tolerance have not been fully elucidated. The purpose of the study was to evaluate the effects of the orexin-1 and orexin-2 receptor (OX1R and OX2R) agonist and antagonist on morphine analgesia and tolerance in rats.Material and methodsA total of 90 Wistar albino male rats weighing 180–220 g were used in the experiments. To induce morphine tolerance, rats were injected with a single dose of morphine (50 mg kg−1, s.c.) for 3 days. Morphine tolerance was assessed on day 4 in randomly selected rats by analgesia tests. In order to evaluate morphine tolerance situation, orexin-A, SB-334867, orexin-B and TCS OX2 29 were administered together with morphine for 3 days. The analgesic effects of orexin-A (10 μg kg−1), OXR1 antagonist SB-334867 (10 mg kg−1), OXR2 agonist orexin-B (15 μg kg−1), OXR2 antagonist TCS OX2 29 (0.5 mg kg−1) and morphine (5 mg kg−1) were measured at 15 or 30-min intervals by tail-flick and hot-plate antinociceptive tests.ResultsThe results suggested that the combination of orexin-1 receptor antagonist SB-334867 and orexin-B with morphine significantly increased the analgesic effect compared to morphine-tolerant rats. In addition, administration of orexin-A and -B alone showed significant analgesic effects compared to the saline group. However, co-administration of orexin-A and -B with morphine did not increase the analgesic efficacy of morphine.ConclusionsThe results of this study demonstrated that co-administration of SB-334867 and orexin-B with morphine attenuated morphine tolerance. Further studies are needed to elucidate the details of the interaction between orexin receptors and the opioidergic system.