Received for publication April 14, 2006.
Revised July 17, 2006.
Accepted for publication July 20, 2006.

Diabetes-induced mechanical hyperalgesia involves spinal MAPKs activation in neurons and microglia via NMDA-dependent mechanisms

Abstract

Molecular mechanisms underlying diabetes-induced painful neuropathy are poorly understood. In the streptozotocin-induced diabetic rats, we have demonstrated that mechanical hyperalgesia, a common symptom of diabetic neuropathy, was correlated with an early increase of ERK, p38 and JNK phosphorylation in the spinal cord and dorsal root ganglion at three weeks of the diabetes. This change was specific of hyperalgesia because non hyperalgesic rats failed to have such an increase. Immunoblots 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 MAPKs colocalized both with the neuronal (NeuN) and microglial (OX42) cell-specific markers but not with the astrocyte marker (GFAP) in the superficial dorsal horn-laminae of the spinal cord. In these same rats, a seven-day administration (5 µg/rat/day, i.t.) of U0126, SB203580 and SP600125, which inhibit MEK, 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 seven days by MK801 (5 µg/rat/day, i.t.), a non-competitive 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 chronic maintenance of painful diabetic hyperalgesia and that these kinases represent potential targets for pain therapy.

Key words: Glutamate, MAP Kinase, Jun Kinase, P38 MAP Kinase, Synaptic plasticity

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