title: Neuron-astrocyte signaling network in spinal cord dorsal horn mediates painful neuropathy of type 2 diabetes.
abstract: Activation of the neuronal-glial network in the spinal cord dorsal horn (SCDH) mediates various chronic painful conditions. We studied spinal neuronal-astrocyte signaling interactions involved in the maintenance of painful diabetic neuropathy (PDN) in type 2 diabetes. We used the db/db mouse, an animal model for PDN of type 2 diabetes, which develops mechanical allodynia from 6 to 12 wk of age. In this study, enhanced substance P expression was detected in the presynaptic sensory fibers innervating lamina I-III in the lumbar SCDH (LSCDH) of the db/db mouse at 10 wk of age. This phenomenon is associated with enhanced spinal ERK1/2 phosphorylation in projection sensory neurons and regional astrocyte activation. In addition, peak phosphorylation of the NR1 subunit of N-methyl-D-aspartate receptor (NMDAR), along with upregulation of neuronal and inducible nitric oxide synthase (nNOS and iNOS) expression were detected in diabetic mice. Expression of nNOS and iNOS was detected in both interneurons and astrocytes in lamina I-III of the LSCDH. Treatment with MK801, an NMDAR inhibitor, inhibited mechanical allodynia, ERK1/2 phosphorylation, and nNOS and iNOS upregulation in diabetic mice. MK801 also reduced astrocytosis and glial acidic fibrillary protein upregulation in db/db mice. In addition, N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor, had similar effects on NMDAR signaling and NOS expression. These results suggest that nitric oxide from surrounding interneurons and astrocytes interacts with NMDAR-dependent signaling in the projection neurons of the SCDH during the maintenance of PDN.
authors.affiliation: Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109-2200, USA.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Dauch
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Yanik
authors.forename: Wilson
authors.initials: W
authors.lastname: Hsieh
authors.forename: Sang Su
authors.initials: SS
authors.lastname: Oh
authors.forename: Hsinlin T
authors.initials: HT
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester