Abstract
BackgroundSpinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1).MethodsColonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western blot and immunohistochemistry. Signal transduction was studied by direct examination and use of specific inhibitors.ResultsDuring colitis, the level of NR1 phospho-Ser896 was increased in the dorsal horn region of the L1 and S1 spinal cord; this increase was attenuated by injection of BDNF neutralizing antibody to colitic animals (36 μg/kg, intravenous (i.v.)) and was also reduced in BDNF+/− rat treated with TNBS. Signal transduction examination showed that the extracellular signal-regulated kinase (ERK) activation was not involved in BDNF-induced NR1 phosphorylation. In contrast, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediated BDNF-induced NR1 phosphorylation in vivo and in culture; this is an additional pathway to the phospholipase C-gamma (PLCγ) and the protein kinase C (PKC) that was widely considered to phosphorylate NR1 at Ser896. In spinal cord culture, the inhibitors to PLC (U73122), PKC (bisindolylmaleimide I), and PI3K (LY294002), but not MEK (PD98059) blocked BDNF-induced NR1 phosphorylation. In animals with colitis, treatment with LY294002 (50 μg/kg, i.v.) blocked the Akt activity as well as NR1 phosphorylation at Ser896 in the spinal cord.ConclusionBDNF participates in colitis-induced spinal central sensitization by up-regulating NR1 phosphorylation at Ser896. The PI3K/Akt pathway, in addition to PLCγ and PKC, mediates BDNF action in the spinal cord during colitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0371-z) contains supplementary material, which is available to authorized users.
Highlights
Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity
Up-regulation of NMDA receptor 1 (NR1) phosphorylation at Ser896 in spinal dorsal horn during colitis The expression level and the distribution pattern of the phospho (p)-NR1 in the spinal cord were examined by western blot and immunohistochemistry
It is noteworthy that we have identified that phosphorylation of Ser897 of the NR1 subunit in the spinal cord was regulated by calcitonin gene-related peptide (CGRP) [5]
Summary
Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. Alterations in the expression and activity levels of neurochemical compounds and ion channels in the spinal dorsal horn underlie the molecular mechanisms of spinal central sensitization and is modulated by release of neurotransmitters from the primary sensory neurons located in the dorsal root ganglia (DRG) [4, 5] Following colonic inflammation such as colitis induced by chemicals including trinitrobenzene sulfonic acid (TNBS), zymosan, acetic acid, mustard oil, or dextran sulfate sodium, there are increased levels of neurotrophins and neuropeptides in the DRG and the spinal cord resulting in visceral hypersensitivity [6,7,8,9,10]. We speculate that brain-derived neurotrophic factor (BDNF) may be involved in PKC-mediated NR1 Ser896 phosphorylation in the spinal cord during visceral inflammation
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