A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro

Abstract

A major role of local acidosis in long lasting excitation and sensitization of cutaneous nociceptors has recently been demonstrated. In inflamed tissue, acid pH meets with a mixture of inflammatory mediators which, by themselves, stimulate nociceptors though being subject to profound tachyphylaxis. We have mimicked this condition in a rat skin-saphenous nerve preparation in vitro which allows direct application of chemicals to the isolated receptive fields at the corium side. Stimulant solutions used were CO2-saturated 'synthetic interstitial fluid' (CO2-SIF, pH 6.1), an 'inflammatory soup' (IS) in submaximal concentration containing bradykinin, 5-HT, histamine, prostaglandin E2 (all 106 M in SIF at 38.5°C and pH 7.0), and a combination made of CO2-saturated IS (CO2-1S, pH 6.1). Identified mechanoheat sensitive ('polymodal') C-fiber terminals (n = 36) were treated with these solutions for 5 min at 10 min intervals or for 30 min of sustained stimulation: 20 units responded to CO2-SIF, 12 to IS, whereas 27 units (75%) were excited by CO2-IS. Thus, 6 out of 15 units insensitive to either of the two basic solutions were stimulated by their combination. This enhanced effect of CO2-IS was also expressed in shorter latencies (than with CO2- SIF) and in a significantly larger mean response magnitude of the fiber population: 152 spikes with the combination versus 45 spikes evoked by IS and 93 spikes by CO2-SIF (n = 25; p < 0.002 and < 0.02, respectively, Wilcoxon test). The synergistic interaction between CO2 and IS also showed up during sustained nociceptor stimulation (30 min) by either CO2-SIF (n = 7) or IS (n = 1) when, during the middle 10 min, CO2-IS was applied which significantly increased the discharge. There is a strong, potentially algogenic, interaction between acid pH and inflammatory mediators in terms of prevalence and magnitude of nociceptor excitation. At equal and pathophysiologically relevant concentration, however, hydrogen ions play a dominant role.