title: Activation of the spinal extracellular signal-regulated kinase 5 signaling pathway contributes to morphine physical dependence in rats.
abstract: The activation of mitogen-activated protein kinases (MAPKs) has been observed in synaptic plasticity processes of learning and memory in morphine dependence. However, the role of extracellular signal-regulated protein kinase 5 (ERK5), a member of MAPKs, has not been studied yet in morphine dependence. To identify the function of ERK5 in the formation and development of morphine physical dependence, morphine withdrawal-like behavioral test and western blot technique were used in this research. Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by withdrawal symptoms. In this study, spinal ERK5 signaling pathway was remarkably activated by chronic morphine injection and naloxone-precipitated withdrawal. Intrathecal injection of BIX02188, a novel specific inhibitor of mitogen-activated protein kinases kinase 5 (MEK5), produced a dose- and time-dependent inhibition of the activation of spinal ERK5, without affecting activation of other MAPKs. Moreover, selective attenuation of spinal p-ERK5 expression by BIX02188 could significantly relieve morphine withdrawal symptom, accompanying with the decreased phosphorylation of cAMP response-element binding protein (CREB) in the spinal cord. These findings suggested that activation of the ERK5 signaling pathway might contribute to morphine physical dependence and its specific pharmacological inhibitor BIX02188 could be a potential therapeutic choice for alleviation of morphine withdrawal symptoms in the future.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China.
authors.forename: Chun-Guang
authors.initials: CG
authors.lastname: Wang
authors.forename: Xian-Fu
authors.initials: XF
authors.lastname: Lu
authors.forename: Jing-Qiu
authors.initials: JQ
authors.lastname: Wei
authors.forename: He
authors.initials: H
authors.lastname: Liu
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
authors.forename: Li-Cai
authors.initials: LC
authors.lastname: Zhang
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
mesh_terms: D000704:Analysis of Variance; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009020:Morphine / Q000008:administration & dosage*; D009021:Morphine Dependence / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C533206:BIX 02188; D007211:Indoles; D009020:Morphine; D048054:Mitogen-Activated Protein Kinase 7