title: Blockade of orexin type 1 receptors inhibits the development of morphine tolerance in lateral paragigantocellularis nucleus: an electrophysiological approach.
abstract: Repetitive administration of opioid agonists is associated with the development of tolerance to the effects of these substances and limits their application. Orexin (also known as hypocretin) is involved in morphine tolerance and dependence. The lateral paragigantocellularis nucleus (LPGi) is a key brain region implicated in the tolerance and dependence to opiates. Orexin type 1 receptor (OXR1) has been detected in LPGi nucleus. In this study the effect of OXR1 blockade was investigated on neural activity of LPGi during the development of morphine tolerance in rats. Male Wistar rats weighing 250-300 g were used in this study. To incite tolerance, morphine sulfate was injected intraperitonealy (10 mg/kg, i.p.) once a day for 6 days. A selective OXR1 antagonist (SB-334867) was microinjected into the right cerebral ventricle (10 μg/10 μl, i.c.v.) immediately before each morphine injection. On day 7, the effect of morphine (10 mg/kg, i.p.) on neural activity of LPGi was investigated using in vivo extracellular single unit recording. In this study morphine injection during 6 days led to the development of morphine tolerance in LPGi neurons which was observed as a significant decrease in responsiveness of LPGi neurons to acute morphine injection. Administration of SB-334867 before each morphine injection could reverse the responses of LPGi neurons to acute morphine injection. This study showed that OXR1 blockade by SB-334867 prevents the development of tolerance to morphine in LPGi neurons. Further studies are required to determine molecular and anatomical mediators which are thought to be involved in this phenomenon.
authors.affiliation: Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-331, Tehran, Iran.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Ghaemi-Jandabi
authors.affiliation: Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-331, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Azizi
authors.affiliation: Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-331, Tehran, Iran. Electronic address: ssemnan@modares.ac.ir.
authors.forename: Saeed
authors.initials: S
authors.lastname: Semnanian
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000502:physiology*; D009020:Morphine / Q000494:pharmacology*; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; 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; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D009020:Morphine; D014508:Urea
keywords: Extracellular in vivo single unit recording; LPGi nucleus; Morphine; Orexin; SB-334867; Tolerance