Interactive involvement of BDNF, NGF and CGRP in colonic hypersensitivity in the rat

Laure Delafoy ¹, Agathe Gelot ^2*, Denis Ardid ², Alain Eschalier ², Claude Bertrand ¹, Annette M Doherty ¹ and Laurent Diop ¹

¹ Pfizer Global Research & Development, France
² EA 3848 Pharmacologie médicale Fac Médecine Clermont Ferrand, France

^* To whom correspondence should be addressed. E-mail: agathe.gelot{at}u-clermont1.fr.

Accepted 12 December 2005

Abstract

Background and aims: Neutrophins are involved in the mechanisms of somatic and visceral hypersensitivity. The action of Nerve Growth Factor (NGF) on sensory neurons contributes to the development of referred colonic hypersensitivity induced by Trinitrobenzene Sulfonic Acid (TNBS). According to the data on Brain Derived Neurotrophic Factor (BDNF) and Calcitonin Gene Related Peptide (CGRP) in pain, the aim of the present study was 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 in colonic pain threshold, and finally 3) to investigate the relationship between BDNF, NGF and CGRP by testing anti- neurotrophin antibodies or h-CGRP 8-37 (a CGRP antagonist) on the bowel hypersensitivity induced by these peptides.

Methods: Colonic sensitivity was assessed by 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, respectively, versus a vehicle score of around 18 mm Hg, p<0.001). BDNF (1 to 100 ng/rat, i.p.) 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 versus 18.7 ± 0.7 mm Hg, p<0.001, anti-NGF versus vehicle). NGF-induced colonic hypersensitivity was reversed by h-CGRP 8-37 but not by the anti-BDNF antibody. Finally, neither anti- neurotrophin antibody was able to reverse CGRP-induced colonic hypersensitivity (at a dose of 1µg/kg i.p.).

Conclusion: Systemic BDNF, NGF and CGRP are able to 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.

Keywords: colonic distension, irritable bowel syndrome, neurotrophins, neuropeptide, rats

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Robin Spiller and Alastair Watson
Gut 2006 55: 905. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Gaman, A., Bucur, M. C., Kuo, B. (2009). Review: Therapeutic advances in functional gastrointestinal disease: irritable bowel syndrome. Therapeutic Advances in Gastroenterology 2: 169-181 [Abstract]  
• Klinger, M. B., Vizzard, M. A. (2008). Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis. Am. J. Physiol. Renal Physiol. 295: F1778-F1789 [Abstract] [Full Text]  
• Lynn, P. A., Chen, B. N., Zagorodnyuk, V. P., Costa, M., Brookes, S. J. H. (2008). TNBS-induced inflammation modulates the function of one class of low-threshold rectal mechanoreceptors in the guinea pig. Am. J. Physiol. Gastrointest. Liver Physiol. 295: G862-G871 [Abstract] [Full Text]  
• De Schepper, H. U., De Man, J. G., Ruyssers, N. E., Deiteren, A., Van Nassauw, L., Timmermans, J.-P., Martinet, W., Herman, A. G., Pelckmans, P. A., De Winter, B. Y. (2008). TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 294: G245-G253 [Abstract] [Full Text]  
• Hauer, J. M., Wical, B. S., Charnas, L. (2007). Gabapentin Successfully Manages Chronic Unexplained Irritability in Children With Severe Neurologic Impairment. Pediatrics 119: e519-e522 [Abstract] [Full Text]