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Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms.
Mol Pharmacol. 2006 Oct; 70(4):1246-54.MP

Abstract

Molecular mechanisms underlying diabetes-induced painful neuropathy are poorly understood. We have demonstrated, in rats with streptozotocin-induced diabetes, that mechanical hyperalgesia, a common symptom of diabetic neuropathy, was correlated with an early increase in extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord and dorsal root ganglion at 3 weeks after induction of diabetes. This change was specific to hyperalgesia because nonhyperalgesic rats failed to have such an increase. Immunoblot analysis showed no variation of protein levels, suggesting a post-translational regulation of the corresponding kinases. In diabetic hyperalgesic rats, immunocytochemistry revealed that all phosphorylated mitogen-activated protein kinases (MAPKs) colocalized with both the neuronal (NeuN) and microglial (OX42) cell-specific markers but not with the astrocyte marker [glial fibrillary acidic protein (GFAP)] in the superficial dorsal horn-laminae of the spinal cord. In these same rats, a 7-day administration [5 microg/rat/day, intrathecal (i.t.)] of 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), and anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), which inhibited MAPK kinase, p38, and JNK, respectively, suppressed mechanical hyperalgesia, and decreased phosphorylation of the kinases. To characterize the cellular events upstream of MAPKs, we have examined the role of the NMDA receptor known to be implicated in pain hypersensitivity. The prolonged blockade of this receptor during 7 days by (5R, 10S)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK801; 5 microg/rat/day, i.t.), a noncompetitive NMDA receptor antagonist, reversed hyperalgesia developed by diabetic rats and blocked phosphorylation of all MAPKs. These results demonstrate for the first time that NMDA receptor-dependent phosphorylation of MAPKs in spinal cord neurons and microglia contribute to the establishment and longterm maintenance of painful diabetic hyperalgesia and that these kinases represent potential targets for pain therapy.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale U766, Facultéde de Médecine, Laboratoire de Pharmacologie, 28 Place Henri Dunant, BP38, 63001 Clermont-Ferrand Cedex 1, France. laurence.daulhac@u-clermont1.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16868181

Citation

Daulhac, Laurence, et al. "Diabetes-induced Mechanical Hyperalgesia Involves Spinal Mitogen-activated Protein Kinase Activation in Neurons and Microglia Via N-methyl-D-aspartate-dependent Mechanisms." Molecular Pharmacology, vol. 70, no. 4, 2006, pp. 1246-54.
Daulhac L, Mallet C, Courteix C, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol. 2006;70(4):1246-54.
Daulhac, L., Mallet, C., Courteix, C., Etienne, M., Duroux, E., Privat, A. M., Eschalier, A., & Fialip, J. (2006). Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Molecular Pharmacology, 70(4), 1246-54.
Daulhac L, et al. Diabetes-induced Mechanical Hyperalgesia Involves Spinal Mitogen-activated Protein Kinase Activation in Neurons and Microglia Via N-methyl-D-aspartate-dependent Mechanisms. Mol Pharmacol. 2006;70(4):1246-54. PubMed PMID: 16868181.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. AU - Daulhac,Laurence, AU - Mallet,Christophe, AU - Courteix,Christine, AU - Etienne,Monique, AU - Duroux,Eliane, AU - Privat,Anne-Marie, AU - Eschalier,Alain, AU - Fialip,Joseph, Y1 - 2006/07/25/ PY - 2006/7/27/pubmed PY - 2006/12/9/medline PY - 2006/7/27/entrez SP - 1246 EP - 54 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 70 IS - 4 N2 - Molecular mechanisms underlying diabetes-induced painful neuropathy are poorly understood. We have demonstrated, in rats with streptozotocin-induced diabetes, that mechanical hyperalgesia, a common symptom of diabetic neuropathy, was correlated with an early increase in extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord and dorsal root ganglion at 3 weeks after induction of diabetes. This change was specific to hyperalgesia because nonhyperalgesic rats failed to have such an increase. Immunoblot analysis showed no variation of protein levels, suggesting a post-translational regulation of the corresponding kinases. In diabetic hyperalgesic rats, immunocytochemistry revealed that all phosphorylated mitogen-activated protein kinases (MAPKs) colocalized with both the neuronal (NeuN) and microglial (OX42) cell-specific markers but not with the astrocyte marker [glial fibrillary acidic protein (GFAP)] in the superficial dorsal horn-laminae of the spinal cord. In these same rats, a 7-day administration [5 microg/rat/day, intrathecal (i.t.)] of 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), and anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), which inhibited MAPK kinase, p38, and JNK, respectively, suppressed mechanical hyperalgesia, and decreased phosphorylation of the kinases. To characterize the cellular events upstream of MAPKs, we have examined the role of the NMDA receptor known to be implicated in pain hypersensitivity. The prolonged blockade of this receptor during 7 days by (5R, 10S)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK801; 5 microg/rat/day, i.t.), a noncompetitive NMDA receptor antagonist, reversed hyperalgesia developed by diabetic rats and blocked phosphorylation of all MAPKs. These results demonstrate for the first time that NMDA receptor-dependent phosphorylation of MAPKs in spinal cord neurons and microglia contribute to the establishment and longterm maintenance of painful diabetic hyperalgesia and that these kinases represent potential targets for pain therapy. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16868181/Diabetes_induced_mechanical_hyperalgesia_involves_spinal_mitogen_activated_protein_kinase_activation_in_neurons_and_microglia_via_N_methyl_D_aspartate_dependent_mechanisms_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16868181 DB - PRIME DP - Unbound Medicine ER -