Mathylglyoxal - Effects on Nociceptive NeuronsMechanisms of Sensitization, Hyperexcitability and Inaktivation

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Diabetes is a common cause for polyneuropathy in the western world. Diabetic neuropathy (DN) is characterized by the simultaneous incidence of positive and negative symptoms. Negative symptoms are i.e. concerning the autonomous nervous system gastroparesis and in the somatosensory system an impairment of warm-cold discrimination. Positive symptoms are spontaneous pain, most often of a burning character and/or paresthesia. This indicates sensitization and hyperexcitability on one hand and de-sensitization or degeneration of peripheral nociceptors and autonomous neurons on the other. We demonstrated that Methylglyoxal (MG), an endogenous metabolite, is found in higher quantities mainly in the plasma of patients with painful diabetic neuropathy. We also found that MG activates the chemo- and cold sensitive ion channel TRPA1 by posttranslational modification. We also found that MG activates the chemo- and cold sensitive ion channel TRPA1 by posttranslational modification. It also increases the activation of the sodium channel subtype 1.8 and decreases activation of the subtype 1.7. These modifications could account for activation, sensitization and hyperexcitability of neurons as well as for their desensitization and thus for the positive and negative symptoms of the patients with DN. We expect, that human nociceptors, especially "silent" nociceptors (CMi) become hyperexcitable, whereas autonomous neurons that do not express sodium channel subtype 1.8 and TRPA1 become hypoexcitable. Some time ago, before MG was described as a diabetic neuromodulator, we already used microeurography to demonstrate that CMi are spontaneously active and sensitized in patients with DN. In our current project we plan to investigate MG effects on peripheral neurons especially by electrophysiological techniques on cellular level, animal models and also via mircroneurography in human healthy subjects and patients with DN. We will use receptor- or ion channel deficient mice as well as mice with constitutively high MG plasma level to investigate MG effects on sensory neurons. These results will be compared and correlated to the findings from corresponding experiments done in human. Human psychophysiological experiments will further investigate the translational aspects of the algogenic and sensitizing actions of MG. Another aim of the project is to elucidate synergistic effects of other diabetic and inflammatory mediators and MG.This project aims to uncover mechanisms in a translational approach form bench to beside, which contribute to the symptoms of diabetic neuropathy in humans.