Background & Aims
Itch and Pain are distinct sensations resulting from the central integration of peripheral nerve signals. Both itch and pain evoking chemicals activate the same peripheral neurons, the class of mechano-sensitive C-fibers (CM), which are also activated by noxious heat (1). It is still not clear how itch and pain are signaled differentially by the same nerve fibers. We described recently that CM might encode differences between itch and pain in temporal action potential discharge patterns. Nonhistaminergic pruritogens induce a slow bursting pattern in around 30% CM in humans, which was not described for algogens. Temporal discharge patterns, although extensively studied in other disciplines such as the auditory system, shape crucially synaptic transmission. However, in pain/ itch research, this issue has been neglected. We show now analyses of temporal discharge patterns of peripheral nerve fibers in human evoked chemically and by heat as example for pattern encoding in pain and itch(2)
Methods
Our study uses microneurography to record action potentials from single afferent CM-fibers in five human volunteers induced by various chemical substances (BAM8-22, beta alanine, and ET 1) and heat. The signals were recorded by custom-made software DAPSYS and Spike2 in parallel. The substances cause mixed pain/itch sensations with different ratios of pain and itch. The data was analyzed using the traditional marking method and spike sorting algorithms of spike 2 software. The marking method identified fibers showing a “bursting” discharge pattern. Sorted spikes were further analyzed for temporal patterns using the “spikelet method”(3). A spikelet consists of three consecutive spikes and is characterized by 2 parameters: length and regularity. Spikelet regularity pertains to the consistency of three consecutive spikes occurring at equidistant intervals. Spikelet length, on the other hand, denotes the proximity between these three spikes(3). Data were visualized using 2D heatmaps.
Results
The marking method revealed that in most individual CM fibers, different substances induced either “slow bursting” or “non-bursting” temporal discharge patterns for all tested pruritogens in a tested CM. When analyzing the temporal discharge patterns in selected nerve fibers with excellent recording quality using the spikelet method, distinct differences between the two firing patterns were obvious: The “slow bursting” firing pattern has a very high regularity in comparison to the “non-bursting” firing pattern. Minor differences in both spikelet regularity and length exist between the substances regarding single bursts. When comparing in single fibers the heat and chemically evoked discharges the chemical burst is characterized by high regularity and lower spikelet length in contrast to the heat evoked spikelets. The chemicals evoked mainly itch whereas heat caused pain.
Conclusions
We showed for the first time detailed analyses of temporal discharge patterns in human CM fibers evoked by chemical pruritogens and painful heat. The discharge patterns from CM reacting to non-histaminergic pruritogens with slow bursting discharges, show a highly regular spike activity with higher frequencies as compared to fibers showing a non-bursting discharge pattern. CM, which exhibit a bursting pattern to pruritogens, have a different temporal discharge pattern when activated by noxious heat causing pain. This points towards a modality-specific temporal encoding in peripheral human C-polynociceptors. Further studies are needed to scrutinize temporal discharge patterns in respect to the perceived sensation of itch and pain and also in patient suffering from chronic itch and pain.
References
1.Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M. Separate Peripheral Pathways for Pruritus in Man. J Neurophysiol. Oktober 2008;100(4):2062–9.
2.Fiebig A, Leibl V, Oostendorf D, Lukaschek S, Frömbgen J, Masoudi M, u. a. Peripheral signaling pathways contributing to non-histaminergic itch in humans. J Transl Med. 12. Dezember 2023;21(1):908.
3.Cho K, Jang JH, Kim SP, Lee SH, Chung SC, Kim IY, u. a. Analysis of Nociceptive Information Encoded in the Temporal Discharge Patterns of Cutaneous C-Fibers. Front Comput Neurosci [Internet]. 18. November 2016 [zitiert 31. Januar 2024];10. Verfügbar unter: https://journal.frontiersin.org/article/10.3389/fncom.2016.00118/full