title: The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats.
abstract: The aim of present study was to investigate the involvement of orexin-A neuropeptide in naloxone-induced morphine withdrawal syndrome via modulating neurons bearing GABAA receptors. The locus coeruleus (LC) is a sensitive site for expression of the somatic aspects of morphine withdrawal. Intra-LC microinjection of GABAA receptor agonist attenuates morphine withdrawal signs in rats. Here we studied the influence of LC orexin type 1 receptors blockade by SB-334867 in presence of bicuculline, a GABAA receptor antagonist, on naloxone-induced morphine withdrawal syndrome. Adult male Wistar rats, weighing 250-300 g, were rendered dependent on morphine by subcutaneous (s.c.) injection of increasing morphine doses (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. On 8th day, naloxone (3 mg/kg, s.c.) was injected and the somatic signs of morphine withdrawal were evaluated. Intra-LC microinjections (0.2 μl) of either bicuculline (15 μM) or SB-334867 (3 mM) or a combination of both chemicals were done immediately before naloxone injection. Intra-LC microinjection of bicuculline (15 μM) had no significant effect on morphine withdrawal signs, whereas intra-LC microinjection of SB-334867 considerably attenuated morphine withdrawal signs. However, the effect of SB-334867 in attenuating naloxone-induced morphine withdrawal signs was blocked in presence of bicuculline. This finding, for the first time, indicated that orexin-A may participate in expression of naloxone-induced morphine withdrawal syndrome partly through decreasing the activity of neurons bearing GABAA receptors.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Davoudi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Azizi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Javad
authors.initials: J
authors.lastname: Mirnajafi-Zadeh
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, 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; D001640:Bicuculline / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009287:Naphthyridines; D009292:Narcotic Antagonists / Q000494:pharmacology; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D058787:GABA-A Receptor Antagonists; C578627:Hcrtr1 protein, rat; D009287:Naphthyridines; D009292:Narcotic Antagonists; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D009270:Naloxone; D009020:Morphine; D014508:Urea; D001640:Bicuculline
keywords: GABA(A) receptor; Locus coeruleus; Morphine withdrawal syndrome; Orexin type 1 receptor; Orexin-A