title: Enhancement of μ-opioid receptor desensitization by orexin-A in rat locus coeruleus neurons.
abstract: Opioids have always been used in clinical practice for pain management. However, development of tolerance to their effects following long term administration, seriously restricts further clinical use of these drugs. In this regard, μ-opioid receptor (MOR) desensitization, as an initial step in development of opioid tolerance, is of particular significance. Previous studies support the involvement of orexinergic system in development of opioid tolerance. Locus coeruleus (LC) nucleus has been shown to modulate pain and development of tolerance. Opioid receptors (particularly μ) are densely expressed within the LC. Moreover, it receives widespread orexinergic inputs and orexin type 1 receptors (OX1Rs) are also highly expressed in this brain region. In the present study, the effect of orexin-A (OXA) on met-enkephalin (ME)-induced MOR desensitization was investigated in locus coeruleus neurons of male Wistar rats (2-3weeks of age). ME (30μM), as a potent MOR agonist, was applied for 10min and the outward K+current was recorded using whole cell patch clamp recording. The percentage of decrease in ME-induced K+current was considered as the degree of MOR desensitization. Results indicated that OXA (100nM) enhances ME-induced MOR desensitization via affecting OX1Rs in rat locus coeruleus neurons and this effect is mediated by a protein kinase C dependent mechanism within the LC. The activity of orexinergic system might potentiate the signaling pathways underlying opioid-induced receptor desensitization.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Mohammad Ahmadi Soleimani
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: Narges
authors.initials: N
authors.lastname: Pachenari
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; School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran. Electronic address: ssemnan@modares.ac.ir.
authors.forename: Saeed
authors.initials: S
authors.lastname: Semnanian
mesh_terms: D000818:Animals; D004744:Enkephalin, Methionine / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000068797:Orexins / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000068797:Orexins; D017450:Receptors, Opioid, mu; D004744:Enkephalin, Methionine
keywords: Desensitization; Locus coeruleus; Met-enkephalin; Orexin; μ-Opioid receptor