The interaction between NGF-induced hyperalgesia and acid-provoked pain in the infrapatellar fat pad and tibialis anterior muscle of healthy volunteers

Background: Tissue pH is lowered in inflamed tissues, and the increased proton concentration activates acid-sensing ion channels (ASICs), contributing to pain and hyperalgesia. ASICs can be upregulated by nerve growth factor (NGF). The aim of this study was to investigate two new human experimental pain models combining NGF-and acid-induced pain in a randomized, controlled, double-blind study. Methods: In experiment 1, volunteers (N = 16) received an injection of either NGF or isotonic saline in each infrapatellar fat pad (IFP). One day after 5 mL of phosphate-buffered acidic saline was infused into each IFP at a rate of 20 mL/h. In experiment 2, the tibialis anterior (TA) muscle of additional volunteers (N = 16) was examined, following the same procedure except that the volume and infusion rate of acid were different (10 mL, 30 mL/h). Continuous pain ratings were recorded during and after acid infusions. In addition, soreness scores on a Likert scale and pressure pain thresholds (PPTs) were assessed. Results: The PPT of the IFP was significantly decreased at the NGF injection site on day 1, but acid-provoked pain ratings and the change in PPT from pre- to postinfusion between the knees were similar. In the muscle pain model, local mechanical hyperalgesia developed 3 h after the NGF injection and a significant additional decrease in PPT was found after acid infusion compared to preinfusion. Conclusions: NGF sensitization in the IFP was not facilitated by acid, whereas an acid-provoked enhancement of muscle hyperalgesia was found. NGF sensitization of adipose tissue responds differently to acid provocation compared to muscle tissue. Significance: Quantification of two novel pain models combining NGF and acid. Hyperalgesia developed after NGF injection in the infrapatellar fat pad, but it was not facilitated by acid provocation. Contrary, NGF-induced hyperalgesia in muscle tissue was enhanced by acid.