Interleukin-6 in combination with its soluble IL-6 receptor sensitises rat skin nociceptors to heat, in vivo

Interleukin-6 (IL-6) contributes to increased pain and hyperalgesia in inflamed tissue. We have investigated the effects of IL-6, alone or in combination with its soluble receptor (sIL-6R), on the sensitivity of nociceptors to noxious heat, using dermal microdialysis. Plasmapheresis membranes were inserted into the abdominal skin of adult male Wistar rats (n=46) and perfused with modified Ringer solution. After three control samples (20 min each), the skin area above the membrane was heated to 48 degrees C for 20 min. The stimulation was followed by two washout samples. The calcitonin gene-related peptide (CGRP) content of the dialysate was measured with an enzyme immunoassay. Heat stimulation provoked a significant CGRP increase in the dialysate. Intradermal application of IL-6 (200 ng ml-1) did not significantly alter heat-induced CGRP release. However, a significant sensitisation of the heat-induced CGRP release was observed when sIL-6R (25 ng ml-1) was applied, either alone or in combination with IL-6. Neutralisation of endogenous IL-6 with a sheep anti-rat IL-6 serum did not alter heat-induced CGRP release, but abolished the sIL-6R-mediated sensitising effect. We show that IL-6 in combination with its soluble receptor can sensitise nociceptors to heat and provide evidence for the constitutive expression of the signalling molecule gp130, but not of the IL-6-membrane-bound (specific) receptor, in nociceptors.