title: The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective.
abstract: Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Hakime
authors.initials: H
authors.lastname: Abdollahi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Ghaemi-Jandabi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address: azizih@modares.ac.ir.
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: Saeed
authors.initials: S
authors.lastname: Semnanian
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage; D004361:Drug Tolerance; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D000068796:Orexin Receptor Antagonists / Q000008:administration & dosage; D064446:Orexin Receptors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives
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; LC neurons; Morphine tolerance; Orexin; SB-334867