Neuron-astrocyte signaling network in spinal cord dorsal horn mediates painful neuropathy of type 2 diabetes

• Published in: Glia Vol. 60; no. 9; pp. 1301 - 1315
• Main Authors: Dauch, Jacqueline R., Yanik, Brandon M., Hsieh, Wilson, Oh, Sang Su, Cheng, Hsinlin T.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2012
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - physiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; Dizocilpine Maleate - pharmacology; Enzyme Inhibitors - pharmacology; extracellular signal-regulated kinase; Glial Fibrillary Acidic Protein - metabolism; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; N-methyl-D-aspartate receptor; Nerve Net - drug effects; Nerve Net - metabolism; Nerve Net - physiopathology; neuron-glial interactions; neuropathic pain; NG-Nitroarginine Methyl Ester - pharmacology; nitric oxide synthase; Nitric Oxide Synthase Type I - metabolism; Nitric Oxide Synthase Type II - metabolism; Phosphorylation - drug effects; Posterior Horn Cells - drug effects; Posterior Horn Cells - metabolism; Posterior Horn Cells - physiopathology; Receptors, N-Methyl-D-Aspartate - metabolism; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; Up-Regulation
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22349

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. © 2012 Wiley Periodicals, Inc.