Differential sensitization of silent nociceptors to low pH stimulation by prostaglandin E2 in human volunteers

Abstract

Background: Inflammatory mediators activate and sensitize nociceptors. Tissue acidosis with low pH of 5.5 often accompanies inflammation and could enhance inflammatory pain and sensitization. Methods: Action potentials from single mechano-responsive (CM) and mechano-insensitive (CMi) C-nociceptors of cutaneous fascicles of the peroneal nerve in healthy volunteers were recorded by microneurography. Low pH solutions with and without prostaglandin E2 (PGE2) were injected twice (with an interval of approximately 5 min) into two spots of the receptive fields of C-fibres. Heat thresholds of the C-fibres were obtained before and after each injection. Results: Injections of the low pH solutions immediately induced phasic responses in CM nociceptors, whereas CMi fibres responded after a delay of several seconds with a sustained response. More CMi fibres than CM fibres showed ongoing discharge after low pH injection, but the duration and intensity of the responses to the first low pH injection did not differ between them. Upon repetition, duration and intensity of the pH responses increased more than twofold in CMi fibres only. Furthermore, combined application of pH and PGE2 sensitized the response in CMi fibres only. In contrast, heat activation thresholds were sensitized by the combination of low pH and PGE2 in both fibre classes. Conclusions: Our results confirm nociceptor class independent heat sensitization by PGE2 which is probably mediated by transient receptor potential vanilloid 1 phosphorylation. However, prolonged and increased pain responses in humans upon low pH/PGE2 stimulation appear to be primarily dependent on CMi fibres, whereas CM nociceptors appear crucial for phasic responses.

Group II mGluRs suppress hyperexcitability in mouse and human nociceptors

“…Prostaglandins and other inflammatory mediators increase the activity of peripheral fibers and generate pain, itch, and hyperalgesia in humans and can produce a transient discharge in human DRG neurons [14; 34; 41]. Here we show that PGE 2 alters membrane excitability in cultured human sensory neurons from donors without chronic pain by lowering rheobase and the action potential threshold.…”

Mechano‐sensitive nociceptors are required to detect heat pain thresholds and cowhage itch in human skin

“…The absence of input from TRPV1‐ and ASIC‐positive nociceptors from the blocked NCFL may explain this finding. Recent microneurography studies demonstrated that almost all CMi nociceptors (~90%), but only 50% of mechano‐sensitive C‐fibres responded to the injection of a pH 6 solution with ongoing discharges (Namer et al., ). Accordingly, the pain reduction in the differentially anaesthetized area confirms an important contribution of mechano‐insensitive nociceptors to low pH‐induced pain.…”

The Neurobiology of Pain Perception in Normal and Persistent Pain

“…This prolonged discharge may be responsible for the persistent and sustained pain following an initial noxious stimulus. If the low pH was combined with the inflammatory mediator PGE-2, the silent nociceptors exhibited sensitization after repeated stimuli and responded with greater than twofold increase in duration and intensity [85]. This suggests that under inflammatory conditions, the silent nociceptors remain active with sustained discharge, contributing to the development of chronic pain.…”