title: Spinal D1-like dopamine receptors modulate NMDA receptor-induced hyperexcitability and NR1 subunit phosphorylation at serine 889.
abstract: Activation of the N-methyl-d-aspartate receptor (NMDAR) in dorsal horn neurons is recognized as a fundamental mechanism of central sensitization and pathologic pain. This study assessed the influence of dopaminergic, D1-like receptor-mediated input to the spinal dorsal horn on NMDAR function. Spinal superfusion with selective NMDAR agonist cis-ACPD significantly increased C-fiber-evoked field potentials in rats subjected to spinal nerve ligation (SNL), but not in sham-operated rats. Simultaneous application of D1LR antagonist SCH 23390 dramatically reduced hyperexcitability induced by cis-ACPD. Furthermore, cis-ACPD-induced hyperexcitability seen in nerve-ligated rats could be mimicked in unin-jured rats during stimulation of D1LRs by agonist SKF 38393 at subthreshold concentration. Phosphorylation of NMDAR subunit NR1 at serine 889 at postsynaptic sites was found to be increased in dorsal horn neurons 90 min after SNL, as assessed by increased co-localization with postsynaptic marker PSD-95. Increased NR1 phosphorylation was attenuated in the presence of SCH 23390 in the spinal superfusate. The present results support that D1LRs regulate most basic determinants of NMDAR function in dorsal horn neurons, suggesting a potential mechanism whereby dopaminergic input to the dorsal horn can modulate central sensitization and pathologic pain.
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain.
authors.forename: Zigor
authors.initials: Z
authors.lastname: Aira
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Barrenetxea
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain.
authors.forename: Itsaso
authors.initials: I
authors.lastname: Buesa
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain.
authors.forename: Endika
authors.initials: E
authors.lastname: Martínez
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain. Electronic address: jonjatsu.azkue@ehu.eus.
authors.forename: Jon Jatsu
authors.initials: JJ
authors.lastname: Azkue
mesh_terms: D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D005071:Evoked Potentials; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D021122:Protein Subunits / Q000819:agonists / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries; D012694:Serine / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000503:physiopathology
chemical_list: C409466:NR1 NMDA receptor; D021122:Protein Subunits; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D012694:Serine