Role of brain-derived neurotrophic factor in the pathogenesis of distention-associated abdominal pain in bowel obstruction

Background: Previous studies found that visceral sensitivity is increased in bowel obstruction (BO). We hypothesized that mechanical stress-induced expression of BDNF in smooth muscle cells (SMC) of the distended bowel plays a critical role in visceral hypersensitivity in BO by altering voltage-gated K⁺ channel (K_v) activity in sensory neurons. Methods: Partial colon obstruction was maintained in rats for 7 days. Colon-projecting neurons in the dorsal root ganglia (DRG, T13 to L2) were isolated for electrophysiological and gene expression studies. Key Results: Compared to controls, membrane excitability of colon-projecting DRG neurons was markedly enhanced in BO. The densities of total K_v and transient A-type (I_A) K⁺ currents, but not sustained delayed I_K current, were significantly reduced in the neurons in BO. The mRNA expression of I_A subtype K_v1.4 in colon neurons was down-regulated in BO. Expression of BDNF mRNA and protein was dramatically increased in colonic smooth muscle of the distended segment, but not in the non-distended aboral segment. Mechanical stretch of colon SMC in vitro increased BDNF expression. Treatment with anti-BDNF antibody restored total K_v and I_A currents of neurons from BO rats. Administration of Trk B inhibitor ANA-12 blocked BO-associated changes of neuronal excitability, K_v activity and gene expression in obstruction. Conclusions and Inferences: Mechanical stress-induced expression of BDNF in colon SMC plays a critical role in visceral hypersensitivity in BO by suppressing A-type K⁺ currents and gene expression in sensory nerve. These findings help to identify therapeutic targets for distention-associated abdominal pain in the gut.