Tu1716 A Novel Role for Fibroblast Growth Factor-Inducible Molecule 14 (Fn14) in Regulating Intestinal Injury and Colitis-Associated Tumorigenesis

Abstract

of voltage-gated Ca2+ currents (VGCC) were performed with and without selective mu and delta agonists and antagonists (as a measure of functional activity of MOR and DOR at the plasma membrane). In 13 fast-blue labeled DRG neurons from controls, 54% expressed DORmRNA, 38% expressed MORmRNA and 23% expressed both. Patch clamp experiments revealed that the VGCC in DRG neurons incubated with chronic DSS supernatants were 68% smaller than those incubated with control supernatants (-63.6 ± 8.8 pA/pF vs -197.2 ± 22 pA/pF, n = 28 and 23 respectively, P = 0.0009, unpaired t test). To determine whether MOR and DOR were involved, neurons were incubated with supernatants from control or chronic DSS mice and 100 nM DADLE (delta agonist) or 100 nM DAMGO (mu agonist). DADLE inhibited 60% of voltage-gated Ca2+ in small DRG neurons incubated with control supernatants (-60.5 ± 14 pA/pF vs -197.2 ± 22 pA/pF , n = 11 and 28 respectively P = 0.007, unpaired t test). DAMGO had only a small effect (27% inhibition) in small DRG neurons (-135.3 ± 38 pA/pF vs -197.2 ± 22 pA/pF n = 11 and 28 respectively). In neurons incubated with chronic DSS supernatants neither DADLE nor DAMGO had an effect on VGCC. However, 1 μM CTOP, a selective antagonist of MOR reversed the inhibitory effects of chronic DSS supernatants on Ca2+ currents (-63.6 ± 8.8 pA/pF vs -224.8 ± 34 pA/pF, P = 0.0001), while 1 μM SDM25N, a selective antagonist of DOR, had no effect (-63.6 ± 8.8 pA/pF vs -88.7 ± 28 pA/pF). Our data suggest that chronic DSS inflammation enhanced mu opioid signalling and decreased delta opioid signalling. These changes underscore the importance of differences in opioid signalling during the evolution of inflammation in IBD.