Background & Aims

Reactive carbonyl species (RCS) such as Methlglyoxal (MGO), an endogenous byproduct in the glucose and lipid metabolism, are involved in many complications in metabolic-dysfunction associated diseases such as diabetes. Methylglyoxal activates the chemo- and cold sensitive ion channel TRPA1, increases the activation of the sodium channel subtype 1.8 (Nav 1.8) and decreases activation of the subtype Nav 1.7 (1,2). Single subcutaneous injections of MGO induce dose-dependent pain sensations in healthy human volunteers and especially activate the sub-group of mechano-insensitive C-fibers (CMi) (3). In humans, functionally different nociceptor classes are discussed to express varying Nav isoforms, which could also be differentially affected by MGO. Therefore, this study focuses on assessing the differential effects of MGO on axonal function of C-fibers in healthy human volunteers and in a next step, if RCS correlate with pathological C-fiber changes in patients with metabolic syndrome.

Methods

We performed psychophysical testing including quantitative sensory testing as well as electrical stimulation using different electrical stimuli with a surface electrode on the dorsum of the foot and forearm in healthy volunteers (before and after single and repeated intracutaneous MGO injections) and in patients with metabolic syndrome.
Single nerve fiber recordings of nociceptors of the superficial peroneal nerve (microneurography) at ancle level were performed to investigate thresholds and supra-threshold responses of C-fibers in healthy volunteers (before and after intracutaneous MGO injections) and patients.

Results

In healthy volunteers, in psychophysical tests, we observed differential effects of single and repeated intracutaneous applications of MGO in healthy human subjects. While repeated MGO applications resulted in a significantly reduced chemical and heat pain sensation compared to single MGO stimuli, the opposite effect was observed for a suprathreshold electrical stimulus with a significant increase in NRS-pain rating after repeated MGO application.
In direct assessment of human C-fiber function via microneurography, MGO additionally exerts differential effects on the axonal properties of the different human C-fibers classes. Polymodal CM-fibers show changes in accordance with desensitization, while the “sleeping” CMi-fibers appear sensitized after intracutaneous MGO application.

Conclusions

The results of this study highlight that MGO substantially influences the axonal function of afferent sensory nerve fibers. The MGO effects in psychophysical testing were different for single or repeated application, suggesting that longer-lasting MGO application results in axonal sensitization for suprathreshold electrical stimuli, potentially mediated by effects of MGO on voltage-gated sodium channels (Nav) but also desensitization of pain thresholds, which could be accounted to TRPA1 desensitization.
In microneurography recordings, MGO affected the two main C-fiber classes of CM and CMi differentially, which could again be due to different sodium channel expression and clearly different axonal function of both fiber classes.
In a next step, patient data from psychophysical testing and microneurography will be analyzed correlated to systemic and local levels of RCS, including MGO.

References

1) Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, Haberkorn U, Brownlee M, Reeh PW, Nawroth PP. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med. 2012 Jun;18(6):926-33.
2) Düll MM, Riegel K, Tappenbeck J, Ries V, Strupf M, Fleming T, Sauer SK, Namer B. Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation. Pain. 2019 Nov;160(11):2497-2507.
3) Becker AK, Babes A, Düll MM, Khalil M, Kender Z, Gröner J, Namer B, Reeh PW, Sauer SK. Spontaneous activity of specific C-nociceptor subtypes from diabetic patients and mice: Involvement of reactive dicarbonyl compounds and (sensitized) transient receptor potential channel A1. J Peripher Nerv Syst. 2023 Jun;28(2):202-225.

Presenting Author

Miriam M. Düll

Poster Authors

Miriam Düll

MD, MHBA

Department of Medicine 1, University Hospital Erlangen, Germany

Lead Author

Fabienne Falter

Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg

Lead Author

Anne Bauer

Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg

Lead Author

Andy Fiebig

Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany

Lead Author

Thomas Fleming

Department of Medicine 1, University Hospital Heidelberg

Lead Author

Nurcan Üçeyler

MD

Department of Neurology, University of Würzburg, Germany

Lead Author

Barbara Namer

Institute of Neurophysiology/ IZKF research group neuroscience, Uniklinik RWTH Aachen, Germany

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral