Role of nerve growth factor in the trinitrobenzene sulfonic acid-induced colonic hypersensitivity.
The majority of patients with digestive disorders display visceral pain. In these troubles, visceral pain threshold is decreased, demonstrating visceral hypersensitivity. There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. This hypothesis was tested in a model of colonic hypersensitivity measured by isobaric distension in conscious rats. This study was designed to evaluate (1) the effect of exogenous NGF on colonic pain threshold, (2) the involvement of NGF in trinitrobenzene sulfonic acid (TNBS)-induced colonic hypersensitivity, by testing an anti-NGF antibody, and (3) finally the involvement of sensory nerves on NGF and TNBS effects using rats treated neonatally with capsaicin. Intra-peritoneal injection of NGF (0.1-100 ng/rat) decreased in a dose-related manner colonic pain threshold in naive rats. This effect was reversed by anti-NGF antibody (1/2000; 2 ml/kg). TNBS-induced colonic hypersensitivity was also reversed by anti-NGF antibody (1/2000; 2 ml/kg): 37.7 +/- 1.7 and 17.6 +/- 0.7 mmHg (p<0.01) for anti-NGF antibody- and vehicle-treated group, respectively. Neonatal capsaicin pre-treatment inhibited NGF- and TNBS-induced decrease in colonic pain threshold: 49.4 +/- 5.3 versus 22.3 +/- 1.6 mmHg (p<0.01) for capsaicin versus vehicle in NGF-treated rats and 39.6 +/- 3.3 versus 18.0 +/- 1.0 mm Hg (p<0.001) for capsaicin versus vehicle in TNBS-treated rats. These data suggest that the action of NGF on sensory neurons contributes to the development of visceral hypersensitivity and that anti-NGF strategy may be of some therapeutic benefits in digestive sensory disorders.
Delafoy
Laure
L
Pfizer Global Research and Development, Fresnes Laboratories, 3-9 rue de la Loge, BP 100, 94265 Fresnes Cedex, France INSERM-EMI 9904, Pharmacologie médicale, 28 place H Dunant, BP 38, 63001 Clermont-Ferrand, France.
Raymond
Frederic
F
Doherty
Annette M
AM
Eschalier
Alain
A
Diop
Laurent
L
D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006967:Hypersensitivity / Q000473:pathology; D008297:Male; D020932:Nerve Growth Factor / Q000633:toxicity*; D010146:Pain / Q000139:chemically induced / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*
D014302:Trinitrobenzenesulfonic Acid; D020932:Nerve Growth Factor