title: Endogenous interleukin-1β in neuropathic rats enhances glutamate release from the primary afferents in the spinal dorsal horn through coupling with presynaptic N-methyl-D-aspartic acid receptors.
abstract: Excessive activation of glutamate receptors and overproduction of proinflammatory cytokines, including interleukin-1β (IL-1β) in the spinal dorsal horn, are key mechanisms underlying the development and maintenance of neuropathic pain. In this study, we investigated the mechanisms by which endogenous IL-1β alters glutamatergic synaptic transmission in the spinal dorsal horn in rats with neuropathic pain induced by ligation of the L5 spinal nerve. We demonstrated that endogenous IL-1β in neuropathic rats enhances glutamate release from the primary afferent terminals and non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Myeloid differentiation primary response protein 88 (MyD88) is a mediator used by IL-1β to enhance non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Presynaptic NMDA receptors are effector receptors used by the endogenous IL-1β to enhance glutamate release from the primary afferents in neuropathic rats. This is further supported by the fact that NMDA currents recorded from small neurons in the dorsal root ganglion of normal rats are potentiated by exogenous IL-1β. Furthermore, we provided evidence that functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is mediated by the neutral sphingomyelinase/ceramide signaling pathway. Hence, functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is a crucial mechanism leading to enhanced glutamate release and activation of non-NMDA receptors in the spinal dorsal horn neurons in neuropathic pain conditions. Interruption of such functional coupling could be an effective approach for the treatment of neuropathic pain.
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia 30602.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia 30602.
authors.forename: 喜胜
authors.initials: 喜
authors.lastname: 严
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia 30602.
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia 30602. Electronic address: hrweng@uga.edu.
authors.forename: 汉荣
authors.initials: 汉
authors.lastname: 翁
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D002518:Ceramides; D053583:Interleukin-1beta; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D013108:Sphingomyelin Phosphodiesterase
keywords: Cell Signaling; Glia; Glutamate Receptors Ionotropic (AMPA, NMDA); Pain; Patch Clamp