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TNFα is a key mediator of the pronociceptive effects of mucosal supernatant from human ulcerative colitis on colonic DRG neurons
  1. Charles Ibeakanma,
  2. Stephen Vanner
  1. Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada
  1. Correspondence to Dr Stephen Vanner, 76 Stuart St, GIDRU, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7; vanners{at}hdh.kari.net

Abstract

Objectives 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.

Methods 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 α (TNFα) was studied using TNFα receptor (TNFR) knockout mice and comparing supernatant and TNFα actions.

Results UC supernatants significantly decreased the rheobase and increased action potential discharge, indicating increased neuronal excitability. Human biopsies exhibited high levels of TNFα, and mouse colonic neurons only exhibited TNFR1 mRNA. Incubation with TNFα recapitulated the supernatant effects on neuronal excitability, and supernatant and TNFα actions were almost completely blocked in TNFR knockout mice. In voltage clamp studies, transient IA and IK currents were suppressed and Nav 1.8 currents were enhanced by TNFα and UC supernatant, suggesting that multiple underlying mechanisms contributed to the enhanced excitability.

Conclusions UC supernatants enhance neuronal excitability of sensory dorsal root ganglia neurons innervating the colon. TNFα is a key mediator which acts at neuronal TNFR1 to modulate Kv and Nav currents. Together these data provide a number of potential new targets for pain management in UC.

  • Abdominal pain
  • electrophysiology
  • inflammatory bowel disease TNFα
  • ulcerative colitis

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Footnotes

  • Funding Crohn's and Colitis Foundation of Canada, and Canadian Institutes of Health Research.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Queen's University Human Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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    BMJ Publishing Group Ltd and British Society of Gastroenterology