Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat.
OBJECTIVE
Neutrophins are involved in somatic and visceral hypersensitivity. The action of nerve growth factor (NGF) on sensory neurones contributes to the development of referred colonic hypersensitivity induced by trinitrobenzene sulfonic acid (TNBS). Based on data on brain derived neurotrophic factor (BDNF) and calcitonin gene related peptide (CGRP) in pain, the aims of the present study were: (1) to investigate the involvement of BDNF and CGRP in this model of referred colonic hypersensitivity, (2) to test the effect of exogenous BDNF and CGRP on the colonic pain threshold, and (3) to investigate the relationship between BDNF, NGF, and CGRP by testing antineurotrophin antibodies or h-CGRP 8-37 (a CGRP antagonist) on bowel hypersensitivity induced by these peptides.


METHODS
Colonic sensitivity was assessed using a colonic distension procedure.


RESULTS
Anti-BDNF antibody and h-CGRP 8-37 reversed the induced decrease in colonic threshold (33.4 (2.1) and 40.3 (4.1) mm Hg, respectively, compared with a vehicle score of approximately 18 mm Hg; p<0.001). BDNF (1-100 ng/rat intraperitoneally) induced a significant dose dependent decrease in colonic reaction threshold in healthy rats. This effect was reversed by an anti-BDNF antibody and an anti-NGF antibody (33.4 (0.6) v 18.7 (0.7) mm Hg (p<0.001), anti-NGF v vehicle). NGF induced colonic hypersensitivity was reversed by h-CGRP 8-37 but not by the anti-BDNF antibody. Finally, antineurotrophin antibody could not reverse CGRP induced colonic hypersensitivity (at a dose of 1 microg/kg intraperitoneally).


CONCLUSIONS
Systemic BDNF, NGF, and CGRP can induce visceral hypersensitivity alone and interactively. This cascade might be involved in TNBS induced referred colonic hypersensitivity in which each of these peptides is involved.
Delafoy
L
L
Pfizer Global Research and Development, Fresnes Laboratories, France.
Gelot
A
A
Ardid
D
D
Eschalier
A
A
Bertrand
C
C
Doherty
A M
AM
Diop
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D002404:Catheterization; D003106:Colon / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D043183:Irritable Bowel Syndrome / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D020932:Nerve Growth Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid
D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D014302:Trinitrobenzenesulfonic Acid; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide