TNFalpha is a key mediator of the pronociceptive effects of mucosal supernatant from human ulcerative colitis on colonic DRG neurons.

Abstract

Abdominal pain is a serious cause of morbidity in patients with inflammatory bowel disease. To better understand the mechanisms and potentially identify new targets for treatment, the effects of inflammatory supernatant from colonic biopsies of patients with active ulcerative colitis (UC) on mouse colonic nociceptive dorsal root ganglia neurons were examined. Acutely dissociated dorsal root ganglia neurons innervating the mouse colon were incubated in supernatants obtained from colonic biopsies from patients with UC. Whole-cell patch clamp recordings were obtained to examine the effects on neuronal excitability. The role of tumour necrosis factor alpha (TNFalpha) was studied using TNFalpha receptor (TNFR) knockout mice and comparing supernatant and TNFalpha actions. UC supernatants significantly decreased the rheobase and increased action potential discharge, indicating increased neuronal excitability. Human biopsies exhibited high levels of TNFalpha, and mouse colonic neurons only exhibited TNFR1 mRNA. Incubation with TNFalpha recapitulated the supernatant effects on neuronal excitability, and supernatant and TNFalpha actions were almost completely blocked in TNFR knockout mice. In voltage clamp studies, transient I(A) and I(K) currents were suppressed and Na(v) 1.8 currents were enhanced by TNFalpha and UC supernatant, suggesting that multiple underlying mechanisms contributed to the enhanced excitability. UC supernatants enhance neuronal excitability of sensory dorsal root ganglia neurons innervating the colon. TNFalpha is a key mediator which acts at neuronal TNFR1 to modulate K(v) and Na(v) currents. Together these data provide a number of potential new targets for pain management in UC.