Orexin receptor type-1 antagonist SB-334867 decreases morphine-induced antinociceptive effect in formalin test

Orexin-A and orexin-B are two neuropeptides selectively synthesized in the lateral hypothalamus (LH), a region involved in morphine induced analgesia and pain modulation. Furthermore, orexin-A has been reported to produce an analgesic effect in pain models, which was blocked by orexin-1 receptor antagonist SB-334867, but not naloxone. We studied the effects of intracerebroventricular (ICV) injection of SB-334867, a selective orexin receptor type-1 antagonist, on morphine-induced antinociceptive effect in formalin test in rats. Morphine injection at a dose of 1.5 mg/kg caused a significant decrease in the formalin-induced nociceptive behaviors in phase 1, interphase, and phase 2A, whereas at doses of 3, 6, and 10 mg/kg, a significant reduction in the formalin-induced nociceptive behaviors was observed in all phases. The ICV injection of SB-334867 alone had no effect on the formalin-induced nociceptive behaviors. Pre-treatment with SB-334867 at a dose of 0.5 nmol significantly attenuated the analgesia induced by morphine (at dose 1.5 mg/kg of morphine; interphase and phase 2B and at dose 3 mg/kg of morphine just phase 2B of formalin test). Also, pre-treatment with SB-334867 at a dose of 5 nmol considerably attenuated the morphine-induced analgesia (at dose 1.5 mg/kg of morphine; phase 1, interphase, and phase 2, at dose 3 and 6 mg/kg of morphine just phase 2 of formalin test). Pre-treatment with SB-334867 at a dose of 50 nmol remarkably attenuated the morphine-induced analgesia (at dose 1.5 and 3 mg/kg of morphine; in phase 1, interphase, and phase 2 and also at dose 6 mg/kg of morphine; phase 1 and phase 2B of formalin test). These data suggest that the antinociceptive effects of morphine in formalin test might be associated with orexin receptor type-1. Our findings reveal a new role for the lateral hypothalamus orexin neurons in the morphine-induced analgesia.