title: Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats.
abstract: The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10mg/kg) at set intervals of 12h for 10days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.
authors.affiliation: Physiology- Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Elaheh
authors.initials: E
authors.lastname: Erami
authors.forename: Hassan
authors.initials: H
authors.lastname: Azhdari-Zarmehri
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Rahmani
authors.forename: Elmira
authors.initials: E
authors.lastname: Ghasemi-Dashkhasan
authors.forename: Saeed
authors.initials: S
authors.lastname: Semnanian
authors.forename: Abbas
authors.initials: A
authors.lastname: Haghparast
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009287:Naphthyridines; D009293:Opioid-Related Disorders / Q000503:physiopathology*; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009020:Morphine; D014508:Urea