title: Possible involvement of prolonging spinal µ-opioid receptor desensitization in the development of antihyperalgesic tolerance to µ-opioids under a neuropathic pain-like state.
abstract: In the present study, we investigated the possible development of tolerance to the antihyperalgesic effect of µ-opioid receptor (MOR) agonists under a neuropathic pain-like state. Repeated treatment with fentanyl, but not morphine or oxycodone, produced a rapid development of tolerance to its antihyperalgesic effect in mice with sciatic nerve ligation. Like the behavioral study, G-protein activation induced by fentanyl was significantly reduced in membranes obtained from the spinal cord of nerve-ligated mice with in vivo repeated injection of fentanyl. In β-endorphin-knockout mice with nerve ligation, developed tolerance to the antihyperalgesic effect of fentanyl was abolished, and reduced G-protein activation by fentanyl after nerve ligation with fentanyl was reversed to the normal level. The present findings indicate that released β-endorphin within the spinal cord may be implicated in the rapid development of tolerance to fentanyl under a neuropathic pain-like state.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Japan. narita@hoshi.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ozeki
authors.forename: Megumi
authors.initials: M
authors.lastname: Asato
authors.forename: Mahardian
authors.initials: M
authors.lastname: Rahmadi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sudo
authors.forename: Minoru
authors.initials: M
authors.lastname: Hojo
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy; D007279:Injections, Subcutaneous; D008026:Ligation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010098:Oxycodone / Q000008:administration & dosage / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D012584:Sciatic Nerve / Q000601:surgery; D012965:Sodium Chloride / Q000008:administration & dosage; D013116:Spinal Cord / Q000378:metabolism*; D001615:beta-Endorphin / Q000235:genetics / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012965:Sodium Chloride; D001615:beta-Endorphin; D009020:Morphine; D010098:Oxycodone; D019204:GTP-Binding Proteins; D005283:Fentanyl