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Exp Neurol ; 293: 144-158, 2017 07.
Article in English | MEDLINE | ID: mdl-28412220

ABSTRACT

Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca2+ permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. Levels of GluA1 and GluA4 from dorsal spinal membrane fractions increased in carrageenan-injected rats compared to controls. In the same tissue, GluA2 levels were not altered. Inflammation-induced increases in membrane GluA1 were prevented by i.t. pre-treatment with antagonists to TNF, PI3K, PKA and NMDA. Interestingly, administration of TNF or PI3K inhibitors followed by carrageenan caused a marked reduction in plasma membrane GluA2 levels, despite the fact that membrane GluA2 levels were stable following inhibitor administration in the absence of carrageenan. TNF pre-incubation induced increased numbers of Co2+ labeled dorsal horn neurons, indicating more neurons with Ca2+ permeable AMPAr. In parallel to Western blot results, this increase was blocked by antagonism of PI3K and PKA. In addition, spinal slices from GluA1 transgenic mice, which had a single alanine replacement at GluA1 ser 845 or ser 831 that prevented phosphorylation, were resistant to TNF-induced increases in Co2+ labeling. However, behavioral responses following intraplantar carrageenan and formalin in the mutant mice were no different from littermate controls, suggesting a more complex regulation of nociception. Co-localization of GluA1, GluA2 and GluA4 with synaptophysin on identified spinoparabrachial neurons and their relative ratios were used to assess inflammation-induced trafficking of AMPAr to synapses. Inflammation induced an increase in synaptic GluA1, but not GluA2. Although total GluA4 also increased with inflammation, co-localization of GluA4 with synaptophysin, fell short of significance. Taken together these data suggest that peripheral inflammation induces a PI3K and PKA dependent TNFR1 activated pathway that culminates with trafficking of calcium permeable AMPAr into synapses of nociceptive dorsal horn projection neurons.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Posterior Horn Cells/metabolism , Radiculopathy/pathology , Receptors, AMPA/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Calcium/metabolism , Carrageenan/toxicity , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Etanercept/therapeutic use , Female , Male , Mice , Posterior Horn Cells/pathology , Posterior Horn Cells/ultrastructure , Protein Transport/drug effects , Protein Transport/physiology , Radiculopathy/chemically induced , Radiculopathy/drug therapy , Rats, Sprague-Dawley , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Synaptophysin/metabolism , Tumor Necrosis Factor-alpha/pharmacology
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