MD SP14

Diabetic thin fiber neuropathy – objective assessment and mechanisms

Supervisor (Mannheim): Martin Schmelz
Co-Supervisor (Groningen): Gerbrand J. Groen
Graduate: Julia Filip

Project description

Small fiber diabetic neuropathy is clinically important and advanced glycolysation end products (AGE) such as methylglyoxal have been suggested as its mediators. We hypothesize that methylglyoxal increases neuronal excitability in unmyelinated fibers. Excitability changes of single nociceptors upon acute methylglyoxal challenge will be assessed electrophysiologically in-vivo in the pig. This animal model provides axonal characteristics of unmyelinated nociceptor classes corresponding to human. In addition to suprathreshold responses to mechanical, heat and electrical stimuli also frequency dependent slowing of conduction velocity and conduction failure will be tested in C-afferent and sympathetic fibers. In a translational approach we will use corresponding stimulation protocols in diabetic patients with and without neuropathic pain in order to assess clinical neuronal hyperexcitability and its presumed relation to methylglyoxal levels in the patients.

References

1. Bierhaus A, Fleming T, Brownlee M, Reeh PW, Nawroth PP. Methylglyoxal modification of Na(v)1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012
2. Kalliomaki M, Kieseritzky JV, Schmidt R, Hagglof B, Karlsten R, Sjogren N, Albrecht P, Gee L, Rice F, Wiig M, Schmelz* M, Gordh T. Structural and functional differences between neuropathy with and without pain? Exp Neurol 2011;231:199-206.
3. Kleggetveit IP, Namer B, Schmidt R, Helas T, Ruckel M, Orstavik K, Schmelz* M, Jorum E. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 2012;153:2040-2047.
4. Obreja* O, Ringkamp M, Namer B, Forsch E, Klusch A, Rukwied R, Petersen M, Schmelz* M. Patterns of activity-dependent conduction velocity changes differentiate classes of unmyelinated mechano-insensitive afferents including cold nociceptors, in pig and in human. Pain 2010;148:59-69.
5. Obreja* O, Ringkamp M, Turnquist B, Hirth M, Forsch E, Rukwied R, Petersen M, Schmelz* M. Nerve growth factor selectively decreases activity-dependent conduction slowing in mechano-insensitive C-nociceptors. Pain 2011;152:2138-2146.

*Own publications

Methods used

In vivo electrophysiology in animal models, human pain models, electrophysiology and psychophysics in patients

Collaboration Partners

• Gerbrand Groen, Groningen
• Ellen Jorum, Oslo
• Peter W. Reeh, Erlangen
• PIs of GRK 1874 DIAMICOM in Mannheim, Heidelberg, Groningen