title: Pathogenesis of abdominal pain in bowel obstruction: role of mechanical stress-induced upregulation of nerve growth factor in gut smooth muscle cells.
abstract: Abdominal pain is one of the major symptoms in bowel obstruction (BO); its cellular mechanisms remain incompletely understood. We tested the hypothesis that mechanical stress in obstruction upregulates expression of nociception mediator nerve growth factor (NGF) in gut smooth muscle cells (SMCs), and NGF sensitizes primary sensory nerve to contribute to pain in BO. Partial colon obstruction was induced with a silicon band implanted in the distal bowel of Sprague-Dawley rats. Colon-projecting sensory neurons in the dorsal root ganglia (T13 to L2) were identified for patch-clamp and gene expression studies. Referred visceral sensitivity was assessed by measuring withdrawal response to stimulation by von Frey filaments in the lower abdomen. Membrane excitability of colon-projecting dorsal root ganglia neurons was significantly enhanced, and the withdrawal response to von Frey filament stimulation markedly increased in BO rats. The expression of NGF mRNA and protein was increased in a time-dependent manner (day 1-day 7) in colonic SMC but not in mucosa/submucosa of the obstructed colon. Mechanical stretch in vitro caused robust NGF mRNA and protein expression in colonic SMC. Treatment with anti-NGF antibody attenuated colon neuron hyperexcitability and referred hypersensitivity in BO rats. Obstruction led to significant increases of tetrodotoxin-resistant Na currents and mRNA expression of Nav1.8 but not Nav1.6 and Nav1.7 in colon neurons; these changes were abolished by anti-NGF treatment. In conclusion, mechanical stress-induced upregulation of NGF in colon SMC underlies the visceral hypersensitivity in BO through increased gene expression and activity of tetrodotoxin-resistant Na channels in sensory neurons.
authors.affiliation: Departments of Internal Medicine.
authors.forename: You-Min
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Departments of Internal Medicine.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Departments of Internal Medicine.
authors.forename: John
authors.initials: J
authors.lastname: Winston
authors.affiliation: Surgery and.
authors.forename: Ravi
authors.initials: R
authors.lastname: Radhakrishnan
authors.affiliation: Departments of Internal Medicine.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Sarna
authors.affiliation: Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Li-Yen M
authors.initials: LM
authors.lastname: Huang
authors.affiliation: Departments of Internal Medicine.
authors.forename: Xuan-Zheng
authors.initials: XZ
authors.lastname: Shi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001913:Bowen's Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D003106:Colon / Q000294:innervation / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000906:Antibodies; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; C507811:Scn8a protein, rat; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D020932:Nerve Growth Factor