Vagally dependent protective action of calcitonin gene-related peptide
on colitis
Ludmilla Mazelin
a
, Vassilia Theodorou
b
, Jean Fioramonti
a
, Lionel Bueno
a,
*
a
Neuro-gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, 180 chemin de Tournefeuille, 31931 Toulouse, France
b
Ecole Supe´rieure d’Agriculture de Purpan, 75 voie du TOEC, 31076 Toulouse, France
Received 4 March 1999; accepted 16 June 1999
Abstract
This work evaluates the mechanism of action of calcitonin gene-related peptide (CGRP) on colitis. Firstly, Wistar rats were intraco-
lonically instilled with trinitrobenzenesulfonic acid (TNBS) and IV treated by either
␣
CGRP, or hCGRP(8–37), or by vehicle. The
inflammatory level was evaluated 8 h and 4 days after TNBS. Secondly, intracerebroventricular
␣
CGRP was assessed on the 4-day group
with colitis. Finally, IV
␣
CGRP was administered in vagotomized animals, and tested on the 4-day group with colitis. Colitis was aggravated
by hCGRP(8–37), and decreased by peripheral but not central
␣
CGRP.
␣
CGRP was inactive on inflammatory parameters in vagotomized
colitic rats. This suggests that endogenous peripheral CGRP has an anti-inflammatory role in TNBS-induced colitis, depending upon the
integrity of the vagus. © 1999 Elsevier Science Inc. All rights reserved.
Keywords: CGRP; TNBS colitis; Gut inflammation; Vagus nerve; Myeloperoxidase; Rats
1. Introduction
Calcitonin gene-related peptide (CGRP) is a 37 amino
acid peptide whose structure has been predicted on the basis
of alternative processing of the primary transcript of the rat
calcitonin gene [42]. CGRP and CGRP binding sites were
shown to be widely distributed both in the central and
peripheral nervous system of man [42] and other species
[45]. This supports the possibility of a functional role of this
peptide in different systems, including the central nervous
system (CNS) and the gut. In the CNS, the distribution of
CGRP-like binding sites in a variety of sensory systems of
the brain and spinal cord as well as in thalamic and hypo-
thalamic areas suggests a widespread involvement of CGRP
at the level of the brain in the regulation of body tempera-
ture, food intake, blood pressure, and the release of hor-
mones such as growth hormone or prolactin from the pitu-
itary (see for review Ref. [54]).
The CGRP innervation of the digestive system has a dual
origin: intrinsic (enteric) and extrinsic particularly dense in
primary afferents (vagal and spinal). In the colon, previous
studies have shown that capsaicin treatment, which at high
doses destroys small- to medium-sized primary sensory
neurons, reduced significantly the CGRP-like immunoreac-
tivity, suggesting that the main source of CGRP in the colon
is the sensory afferent system [36]. At the gastrointestinal
level, CGRP is involved in the regulation of gastric and
mesenteric blood flow [16], in the control of gastric acid
secretion [48] and in the modulation of intestinal motility
[13,37].
Previous studies have demonstrated that sensory inner-
vation and neuropeptides play a modulatory role on both the
initiation and the development of inflammatory reactions in
the gut. Indeed, we recently identified that the integrity of
sensory innervation and particularly vagal afferents is es-
sential for protection or repair of the colonic mucosa during
TNBS-induced inflammatory processes [28,49]. The pres-
ence of dense CGRP-like immunoreactivity in population of
cell bodies in vagal nuclei [43] suggests that CGRP may
have a functional role in the protective effect of vagal
afferents in TNBS-induced inflammatory processes. Ac-
cordingly, in an another inflammatory model, systemic li-
popolysaccharide (LPS) administration have been shown to
stimulate CGRP synthesis in the cervical vagus nerve [19].
In some patients with ulcerative colitis or Crohn’s dis-
ease a pronounced decrease in immunoreactive CGRP con-
* Corresponding author. Tel.: ϩ33-561-285-143; fax: ϩ33-561-285-
397.
E-mail address: lbueno@toulouse.infra.fr (L. Bueno)
Peptides 20 (1999) 1367–1374
0196-9781/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved.
PII: S0196-9781(99)00144-8