title: Ca2+ /calmodulin-dependent protein kinase II in spinal dorsal horn contributes to the pain hypersensitivity induced by γ-aminobutyric acid type a receptor inhibition.
abstract: The fast inhibitory synaptic transmission mediated by the γ-aminobutyric acid type A receptor (GABAA R) within spinal dorsal horn exerts a gating control over the synaptic conveyance of nociceptive information from the periphery to higher brain regions. Although a large body of evidence has demonstrated that the impairment of GABAergic inhibition alone is sufficient to elicit pain hypersensitivity in intact animals, the underlying mechanisms remain to be characterized. The present study shows that Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is an important signaling protein downstream of reduced GABAergic inhibition. We found that pharmacological removal of inhibition by intrathecal application of the GABAA R antagonist bicuculline significantly enhanced the autophosphorylation of CaMKII at Thr286 in spinal dorsal horn of mice. In addition to increased CaMKII activity, bicuculline also promoted CaMKII interaction with N-methyl-D-aspartate (NMDA)-subtype glutamate receptors and induced the translocation of CaMKII from cytosolic compartments to the synaptosomal membrane fraction. Immunoblotting analysis revealed that the phosphorylation levels of NMDA receptor NR2B subunit at Ser1303 and of AMPA-subtype glutamate receptor GluR1 subunit at Ser831, two important CaMKII phosphorylation sites, were substantially enhanced after bicuculline application. Behavioral tests illustrated that intrathecal administration of the CaMKII inhibitor KN-93, NMDA receptor antagonist D-APV, or AMPA receptor antagonist GYKI 52466 effectively ameliorated the mechanical allodynia evoked by bicuculline. These data thus indicate that CaMKII signaling is critical for the reduced inhibition to evoke spinal sensitization.
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, People's Republic of China.
authors.forename: Zhan-Wei
authors.initials: ZW
authors.lastname: Suo
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Fan
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Hu
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D001640:Bicuculline
keywords: AMPA receptor; Ca2+/calmodulin-dependent protein kinase II; GABAA receptor; NMDA receptor; pain