Modulation of Human Peripheral Nociceptors by Interleukin–1b

Objectives: Although peripheral interleukin-1b (IL-1b) evokes hyperalgesia, the mechanisms remain unknown. In the central nervous system IL-1b modulates neurons with both stimulatory and inhibitory effects reported (Coogan et al., 1997, Sachs et al., 2002, Ferreira et al., 1988). We tested the hypothesis that IL-1b sensitizes human nociceptors to administration of capsaicin as measured by release of immunoreactive substance P (iSP). We conducted a clinical trial using a newly developed and validated method of collecting isolated terminals of human nociceptors innervating the periodontal ligament of extracted teeth. Method: We obtained IRB approved informed consent from patients undergoing tooth extraction. The apical 6mm of freshly extracted human teeth were sectioned and pulpal tissue was removed (to exclude potential pulpal nociceptor contribution). The isolated root tips were then exposed to IL-1b (1 to 100ng/mL) or vehicle and then both groups were stimulated with capsaicin (25uM for 20 min). Aliquots were acidified and heated (to inactivate peptidases), lyophilized and then assayed by radioimmunoassay for iSP. The data were normalized by calculating iSP release as percentage of total iSP in the tissue and were analyzed by repeated measures ANOVA. Results: The results indicate that capsaicin evokes iSP release and that IL-1b inhibits capsaicin-evoked iSP release. Our results are consistent with IL-1b modulation of TRPV1 similar to its inhibition at CNS of ligand-gated ion channels. Additional experiments exclude alternate hypothesis (protease release, neuronal cytotoxicity, neuropeptide depletion). Conclusion: We conclude that IL-1b modulates peripheral human nociceptors by a novel inhibitory mechanism. Supported by NIDCR Training Grant DE14318 and CoStar summer research program