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Repeated administration of morphine or orexin-A produces tolerance to their antinociceptive effects. We investigated the possible incidence of cross-tolerance between orexin-A and morphine. Adult male Sprague-Dawley rats (200-250 g) were used. Under deep anesthesia, a stereotaxic apparatus was used to implant a 23 G cannula into the lateral ventricle for an intracerebroventricular (ICV) microinjection. The antinociceptive effect of three different doses of orexin-A (5, 20, and 40 µM; dissolved in 5 µl sterile saline; ICV) was examined using the hot-plate test at 15, 30, 60, and 90 min after infusion. To evaluate tolerance, orexin-A (20 µM; ICV) or morphine (10 mg/kg; intraperitoneal) was administered for 7 consecutive days (twice per day) and the analgesic response was assessed at days 1, 4, and 7. Cross-tolerance was investigated at day 8 with a single injection of morphine (10 mg/kg; intraperitoneal) to the repeated orexin-A group and a single microinjection of orexin-A (20 µM; ICV) to the repeated morphine group. Analgesic responses were then examined. Administration of both orexin-A and morphine produced significant antinociception at day 1 (P<0.001 compared with the saline group). However, a significant reduction in the analgesic effects of both morphine and orexin-A appeared at day 7, following repeated administration (P<0.01). Orexin-A microinjection at day 8 in the repeated morphine group did not result in significant antinociception (P>0.05), whereas morphine injection in the repeated orexin-A group at day 8 showed a significant analgesic effect (P<0.001). These results indicate cross-tolerance to the analgesic effect of orexin-A following morphine tolerance.

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Some evidence demonstrates endogenous inhibitory pathways of pain involved in the interphase (phase between early and later phase) of the formalin test. We previously showed that swimming stress modulates the pain-related behaviors during the interphase of the formalin test. In this study, we evaluated the role of the endogenous opioid system in modulating nociceptive responses of the formalin test. Methods: Swim stress was performed in different heights of water (5, 25, 50 cm) in a swimming tank. The mean nociceptive scores were measured during phase 1 (1-7 min), interphase (8-14 min), and phase 2 (15-90 min) of the formalin test. Opioid receptor antagonist, naloxone (3 mg/kg; IP) was injected immediately before swim stress. Results: Swim stress attenuated nociceptive behaviors in the first phase and increased the duration of interphase in the formalin test in a water-height-dependent manner, compared to the control group. Naloxone significantly increased nociceptive behaviors in the first phase, interphase, and the second phase of the formalin test, compared to the control group. Conclusion: Stress could affect the nociceptive response. Swim stress in different heights of water could have different effects on the nociception in different phases of the formalin test. In addition, the involvement of the endogenous opioid system is further demonstrated in the swim stress-induced modulation of pain behaviors in phase 1, phase 2, as well as interphase of formalin test in rats.