title: Activation of the Extracellular Signal-Regulated Kinase in the Amygdale Modulates Fentanyl-Induced Hypersensitivity in Rats.
abstract: Opioid-induced hyperalgesia (OIH) is one of the major problems associated with use of opioids in perioperative and chronic pain management. The mechanism underlying this paradoxical phenomenon needs to be fully elucidated. Laterocapsular division of the central nucleus of amygdale (CeLC) has emerged as an important brain center for pain modulation, so we hypothesize that the activation of extracellular signal-regulated kinase (ERK) in CeLC may modulate OIH through strengthening synaptic transmission between neurons in the CeLC. Phospho-ERK in CeLC was first found to be increased significantly in OIH rats induced by repeated subcutaneous injection of fentanyl. Blockade of this fentanyl-induced ERK activation by microinjection of U0126, an ERK inhibitor, into the CeLC reversed the behavioral hypersensitivity in a dose-dependent manner. In vitro whole-cell recordings evaluating the change in synaptic transmission found that the frequency as well as amplitude of miniature excitatory postsynaptic currents recorded on CeLC neurons from OIH rats were fundamentally increased and were completely reversed by acutely applied U0126 (10 μM in the recording well). In vivo microinjection of U0126 into the CeLC reversed the spinal long-term potentiation in OIH rats. These results showed that fentanyl-induced hypersensitivity may occur partly through the mechanism of ERK activation and followed by the strengthening of synaptic transmission in CeLC neurons.
  
  
  
  This study provides evidence that ERK in the laterocapsular division of the CeLC is a key contributor to the development of fentanyl-induced hypersensitivity. Targeting the superspinal central CeLC can inhibit spinal long-term potentiation and alleviate behavioral hyperreflexia induced by fentanyl.
authors.affiliation: The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China; Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China; Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Yin
authors.affiliation: The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.
authors.forename: Chenhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hemanshu
authors.initials: H
authors.lastname: Rambojan
authors.affiliation: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: luofang0909@hotmail.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Luo
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005283:Fentanyl / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006967:Hypersensitivity / Q000209:etiology* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D009294:Narcotics / Q000633:toxicity*; D009570:Nitriles / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors; D001617:beta-Glucosidase / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009294:Narcotics; D009570:Nitriles; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D001617:beta-Glucosidase; D005283:Fentanyl
keywords: Pain; central amygdaloid nucleus; central nervous system sensitization; extracellular signal-regulated MAP kinases; long-term potentiation; opioid-induced hyperalgesia