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Filaretova LP, Takeuchi K (eds): Cell/Tissue Injury and Cytoprotection/Organoprotection in the Gastrointestinal
Tract: Mechanisms, Prevention and Treatment. Front Gastrointest Res. Basel, Karger, 2012, vol 30, pp 161–169
Analysis of the Effect of Different
Neuropeptides in Gastric Mucosal
Defense Initiated Centrally
Klara Gyires
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University,
Budapest, Hungary
Abstract
Central nervous system has a profound role in regulation of gastric mucosal integrity. Different neuropeptides such as peptide YY, amylin, leptin, ghrelin, opioids (e.g. β-endorphin, deltorphin II, endomorphins), nociceptin, nocistatin, TLQP-21 and substance P were shown to protect the gastric
mucosa in experimental ulcer models given centrally. Most of the neuropeptides induced gastroprotective action in pmolar dose range injected intracerebroventricularly (i.c.v.) or intracisternally (i.c.),
endomorphins and β-endorphin, proved to be effective even in femtomoles. Dorsal vagal complex
and vagal efferents have basic role in conveying the centrally initiated effect to the periphery.
However, the potential role of sympathetic nervous system in centrally-induced mucosal protection
has also been raised. Our previous results showed that the gastroprotective effect of opioid peptides
was reduced significantly but not abolished by bilateral vagotomy. Now it was demonstrated that
the protective effect of [D-Ala (2), D-Leu (5)]-ol-enkephalin (DAGO; 38 pmol), β-endorphin (10 pmol)
and endomorphin-2 (0.1 pmol) injected i.c.v. was highly reduced after chemical sympathectomy by
6-OH dopamine (600 nmol i.c.v.). Simultaneously, the noradrenaline content of nucleus tractus solitarii (NTS) decreased from 1,881 ± 89 to 1,439 ± 154 pg/mg tissue (p< 0.05) in 6-OH dopaminetreated rats. The results indicate that the integrity of the adrenergic system besides the cholinergic
one may also be necessary for the centrally induced gastroprotection. Further research is needed to
reveal the role of sympathetic nervous system as well as the interactions between neuropeptides in
maintaining gastric mucosal integrity and gastric mucosal defense.
Copyright © 2012 S. Karger AG, Basel
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Gastric mucosal barrier to acid involves several layers, the pre-epithelial mucus bicarbonate layer, an epithelial layer, and a post-epithelial layer consisting of blood vessels,
nonepithelial cells, and enteric nerves. The epithelial layer and post-epithelial layer
produces several substances which have basic role in maintaining gastric mucosal
integrity and gastric mucosal defense, such as bicarbonate, mucus, phospholipids,
trefoil peptides, prostaglandins (PGs), heat shock proteins. Gastric mucosal and
submucosal vessels are innervated by primary afferent sensory neurons and nerves
forming a dense plexus at the mucosal base. These nerve endings can sense the pH of
gastric luminal content and entry of acid into the mucosa via acid-sensing channels.
Activation of these nerves is resulted in direct influence of the tone of submucosal
arterioles, which regulate mucosal blood flow. Stimulation of gastric sensory nerves
leads to the release of neurotransmitters such as calcitonin gene-related peptide and
substance P. Calcitonin gene-related peptide (CGRP) exerts a mucosal protective
action, most likely through vasodilatation of submucosal vessels mediated by nitric
oxide (NO) generation [1, 2].
Gastric mucosal integrity can be regulated both centrally and peripherally. In the last
decades increasing number of evidence suggested that central nervous system (CNS)
has a pivotal role in regulation of gastric mucosal integrity. Different brain areas have
been suggested to be involved in centrally induced gastroprotection. Among them, the
hypothalamus and dorsal vagal complex (DVC) seem to have a particularly important
role and well-defined interconnections between neuroendocrine hypothalamus and
the central autonomic system have been described. Descending hypothalamic efferents carry feedback signals to viscerosensory and brainstem catecholaminergic neurons and regulatory inputs to parasympathetic (dorsal vagal nucleus) and sympathetic
(thoracolumbar intermediolateral cell column) preganglionic neurons. These fibers
originate mainly from neurons of the paraventricular, arcuate, perifornical and dorsomedial nuclei and the lateral hypothalamus. Pathways between the hypothalamus
and autonomic centers are bidirectional; the descending axons are mainly peptidergic
(corticotropin-releasing hormone, vasopressin, oxytocin, somatostatin, enkephalin,
pro-opiomelanocortin), while the ascending fibers are both peptidergic (enkephalin,
neuropeptide Y, neurotensin, dynorphins) and catecholaminergic [3].
Gastroprotection, Cholinergic System
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Thyrotropin-releasing hormone (TRH) or its stable analogue RX-77368, injected in
a low (0.5–1.5 ng) nonsecretory dose into the cisterna magna or the dorsal motor
nucleus of vagus was the first neuropeptide that was shown to protect the gastric
mucosa against ethanol injury through stimulation of vagal cholinergic pathways [4,
5]. Hereafter, additional neuropeptides proved to be gastroprotective given centrally,
among others adrenomedullin [6] peptide YY [7] amylin [8], leptin, cholecystokinin
[9], ghrelin [10], opioids, e.g. β-endorphin, deltorphin II, endomorphins [11, 12]
nociceptin, nocistatin [13], TLQP-21, a VGF-derived peptide [14] and substance P
[15]. The effective dose ranges of some selected neuropeptides is summarized in
table 1. As the data show, a majority of neuropeptides induce gastric mucosal protective action given intarcerebroventricularly (i.c.v.) or intracisternally (i.c.) in the
picomolar dose range, and endomorphin and β-endorphin were shown to be effective even in femtomolar doses.
Table 1. Gastroprotective doses of centrally injected neuropeptides in the rat
Compound
Gastroprotective doses,
nmol/rat
Ulcer model
Adrenomedullin
0.075, 0.15 nmol i.c.
ethanol
6
Amylin
0.66, 2.2 μg i.c.v.
(0.168, 0.56 nmol i.c.v.)*
ethanol, indomethacin
8
Ghrelin
600–5,000 ng i.c.v.
(0.18–1.5 nmol i.c.v.)*
ethanol, ischemia
reperfusion
11
Leptin
625 ng i.c.v.
(0.04 nmol i.c.v.)*
ethanol, ischemia
reperfusion
9
Nociceptin, nocistatin
0.2–1 nmol i.c.v.
ethanol
Opioids
Ref. No.
13
ethanol
β-Endorphin
0.0035 nmol i.c.v.
0.0008 nmol i.c.
11, 12
Endomorphins
0.00003–0.01 nmol i.c.v.
PYY
0.047–0.117 nmol i.c.
ethanol
7
Substance P
0.009–0.018 nmol i.c.v.
ethanol
15
TLQP-21
0.8–8 nmol i.c.v.
ethanol
14
TRH, RX 77368
0.5–1.5 ng i.c.
(0.0013–0.004 nmol i.c.)*
ethanol
4
*Calculated from the given values.
Neuropeptides, Centrally Induced Gastroprotection
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The gastroprotective effect of neuropeptides may relate to their anti-secretory
effect. For example, nociceptin, amylin, β-endorphin as well as TLQP-21 induce a
gastroprotective effect and inhibit acid secretion by a central mechanism [16–19].
However, the antisecretory effect does not obviously contribute to the gastroprotective action, since either gastric acid secretion is not involved in the pathomechanism of ulcer model, where neuropeptides were shown to exert protective effect (e.g.
ethanol-induced mucosal damage) or the effective gastroprotective and anti-secretory
dose ranges are different. For example, the gastroprotective doses of nociceptin and
nocisatin are 0.2–1 nmol [13], the antisecretory dose is 10 nmol i.c.v. [16]. Similarly,
the ED50 values of β-endorphin against ethanol-induced lesions given either i.c.v. or
i.c. are 3.5 and 0.8 pmol/rat, respectively, the anti-secretory ED50 value is 250 pmol/
rat i.c.v [11, 18]. On the other hand the anti-secretory and mucosal protective doses
of TLQP-21 are practically the same (ED50: 2.7 and 3.16 nmol i.c.v., respectively) [14,
19]. Similarly, amylin also exerted antisecretory and mucosal protective effects in the
same doses following i.c.v. injection [8, 17].
However, a gastroprotective effect may be accompanied by increased acid secretion as well, e.g. ghrelin given i.c.v. (600–5,000 ng/rat) increased gastrin release,
gastric acid secretion and attenuated gastric lesions induced by ethanol and ischemiareperfusion. Ghrelin-induced protection and accompanying increase in the gastric
blood flow were completely abolished by vagotomy indicating that these actions
involve vagal nerve integrity [10]. The increased gastric acid secretion after its central
administration could be related to elevation of plasma gastrin concentration.
Dorsal vagal complex (dorsal motor nucleus of vagus and nucleus of the solitary
tract) and vagal efferents have a crucial role in conveying the centrally initiated effect
to the periphery [4–7]. The mechanism of the vagally mediated gastroprotective
effect has been well documented in biochemical and pharmacological studies, demonstrating that activation of vagal cholinergic pathways stimulate gastric prostaglandin and nitric oxide release and the effector function of capsaicin-sensitive afferent
fibers containing CGRP [5, 20]. Accordingly, inhibition of the biosynthesis of prostaglandins by non-selective cyclo-oxygenase inhibitor (e.g. indomethacin), inhibition
of NO synthase by NG-nitro-l-arginine or ablation of primary afferents by high dose
of capsaicin or by blocking the CGRP receptors by CGRP8–37, resulted in significant
reduction of the gastroprotective action [4–7, 9–14]. The role of mucosal prostaglandins in the centrally induced gastroprotective effect of ghrelin has been analyzed in
detailed. It was found that ghrelin (4 μg i.c.v.) increased PGE2 in normal mucosa,
whereas it reversed the ethanol-induced PGE2 surge. Indomethacin and SC560 (selective inhibitor of COX-1), but not celecoxib, removed the mucosal protective effect of
ghrelin, consequently, COX-1-derived PGs are mainly involved in ghrelin-induced
gastroprotection [21]. Similarly, the TLQP-21-induced gastroprotective effect against
ethanol was accompanied by a significant increase in gastric PGE2 production linked
to an increase in constitutive cyclo-oxygenase (COX) expression [14].
Other peripheral mechanisms have also been raised to be responsible for the centrally
induced gastric mucosal protection. For example, depletion of non-protein sulfhydryls
by N-ethyl-maleimide removed the amylin-induced gastric mucosal protection against
ethanol-induced gastric injuries indicating that in addition to NO and prostaglandins,
endogenous sulfhydryls also participate in the gastric beneficial effect of amylin [22].
Our recent finding showed that the decreased mucosal CGRP and somatostatin level following oral administration of ethanol was restored by endomorphin-2 (0.1 pmol i.c.v.)
and simultaneously the ethanol-induced gastric lesions were significantly reduced [12].
Gastroprotection, Adrenergic System
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The dorsal motor nucleus of the vagus besides parasympathetic neurons with diverse
neurochemical phenotypes as well. These discrete neurochemical subpopulations
Neuropeptides, Centrally Induced Gastroprotection
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may provide central modulation of gastric functions. For example, neurons showing
tyrosine hydroxylase immunoreactivity (TH-IR) can be detected in DMV. Moreover,
the population of dopamine β-hydroxylase (DβH) and TH-IR neurons in the dorsal vagal complex were almost identical in number and distribution, suggesting
that the TH-IR positive neurons in the DMV are able to synthesize norepinephrine.
Furthermore, these TH-IR-positive caudal DMV neurons have been shown to display
choline acetyltransferase activity as well [data from ref. 23]. These data may argue
that activation of DVC results in activation of both the cholinergic and adrenergic
system to the peripheral targets. In addition, besides TH-IR neurons it was shown
that a subpopulation of DMV neurons containing nitric oxide synthase immunoreactivity (NOS-IR) projects selectively to the gastric fundus. These neurons have role in
vagally mediated gastric relaxation [23]. The vagally mediated gastric relaxation may
contribute to gastroprotective effect, since it was demonstrated that gastric hypermotility may cause gross damage in the stomach, supporting the importance of gastric motility as a pathogenic element of gastric lesions [24]. Moreover, it also might
be raised if, these NOS-IR neurons by generation of NO mediate not only gastric
relaxation but might affect gastric mucosal microcirculation as well. Consequently,
it should be kept in mind, that surgical vagotomy results in the blockade of both
cholinergic, adrenergic and nitrergic neuronal projection to the periphery and the
vagotomy-induced change in mucosal protection is the results of elimination of these
regulatory pathways.
Activity of dorsal vagal complex may be influenced by neuronal projections from
different brain areas. For example, C3 neurons are one of three known adrenergic
nuclei in the rat central nervous system. Selective tracing of C3 efferents throughout
the rat CNS could be demonstrated, and highest densities of C3 axon varicosities
were observed (besides other brain areas) in the dorsomedial medulla (nuclei of the
solitary tract, area postrema, and the dorsal motor nucleus of the vagus), indicating
the association between adrenergic system and dorsal vagal complex [25].
In the periphery, colocalization of the neurotransmitter receptors for the cholinergic, adrenergic and dopaminergic nerve fibers was observed throughout the
stomach wall. The role of cholinergic system in gastric mucosal defense has been
well documented (see above). However, the involvement of the sympathetic nervous
system in the pathogenesis and cytoprotective action in the gastric mucosa remains
controversial. Ko and Cho [26] showed that neither blockade of the α1-, β1- and
β2-adrenoceptors influenced the ulcerogenic action of 100% ethanol, nor did they
affect the adaptive cytoprotection of mild irritants. On the contrary, isoprenaline,
a β-adrenoceptor agonist, reduced dose-dependently the ethanol-induced mucosal
injury and this effect was accompanied by an elevation of the gastric blood flow.
Suppression of nitric oxide (NO) synthase or sensory denervation with capsaicin
attenuated significantly the isoprenaline-induced gastroprotection and elevation of
gastric blood flow. Consequently, the β-adrenoceptor-induced mucosal protection is
likely to be mediated by NO and sensory neuropeptides [27].
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The role of sympathetic nervous system in centrally initiated gastric mucosal
protection has been demonstrated by pharmacological/surgical analyses as well. For
example angiotensin II injected into the paraventricular nuclei dose-dependently
inhibited gastric ischemia/reperfusion-induced injury, and the protective effect
of angiotensin II was not affected by subdiaphragmatic vagotomy or atropine, but
was abolished by propranolol or disconnection of the nerves innervating the adrenal glands indicating that the central effects of angiotensin II are mediated in the
periphery by a sympathetic-adrenal gland/beta-adrenoceptor pathway [28]. The gastroprotective effect of nociceptin against ethanol administered either i.c.v. (3 μg/rat)
or intaperitoneally (i.p.) (10 μg/kg) was blocked by atropine, subdiaphragmatic vagotomy and bretylium, suggesting that both vagal cholinergic and sympathetic pathways mediate the central activity of this peptide [29].
The role of sympathetic nervous system in centrally induced gastroprotection
was confirmed also by our present findings. Previously, it was shown that i.c.v. and
i.c. injections of opioid peptides produced a dose-dependent inhibition of acidified ethanol-induced gastric mucosal damage [11]. The gastroprotective effect was
reduced following bilateral cervical vagotomy, indicating that integrity of vagal nerve
is necessary for the gastroprotective action of opioids. However, vagotomy did not
result in a complete block of the protective effect of opioids, therefore we examined
the potential role of central adrenergic system in the gastroprotective action of opioid peptides. After chemical sympathectomy by 6-OH dopamine (600 nmol i.c.v.)
the gastroprotective effect of [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAGO) (38
pmol), β-endorphin (10 pmol) and endomorphin-2 (0.1 pmol) was highly reduced
(fig. 1). Simultaneous measurement of the noradrenaline content in the nucleus of
the solitary tract (NTS) showed that the noradrenaline content decreased from 1,881
± 89 to 1,439 ± 154 pg/mg tissue (p < 0.05) in 6-OH dopamine-treated rats (fig. 2.)
indicating that the decrease of the mucosal protective effect of opioid peptides after
6-OH dopamine treatment relates to the reduction of noradrenaline content in the
nucleus of solitary tract. Consequently, it may be concluded that besides the cholinergic system, the integrity of adrenergic system could also be necessary for the
development of centrally induced gastroprotection.
In addition, to determine the role and function of neuropeptides in gastric mucosal
defense the complex, diverse interactions among different neuropeptides should also
be considered. For example, our previous results showed the gastroprotective effect of
nociceptin and nocistatin is likely to be mediated by opioid peptides [13]. Moreover,
centrally injected ghrelin resulted in increased plasma level of gastrin [10], and the
anti-secretory effect of TLQP-21 a VGF-derived peptide, was prevented by cysteamine, a depletor of somatostatin indicating that the central inhibitory effect of TLQP-21
on gastric acid secretion is mediated by endogenous somatostatin [19].
Neuropeptides may also modify the different hormone-induced responses
in gastrointestinal tract. For example, activation of the hypothalamic-pituitaryadrenocortical axis during stress results in acute rise of corticosterone, which is a
6-OHDA
600 nmol/rat i.c.v.
Vehiculum
100
80
###
Ulcer index
###
#
60
**
40
*** ***
20
0
Saline
DAGO 38 pmol/rat i.c.v.
␤-Endorphin 10 pmol/rat i.c.v.
Endomorphin-2 0.1 pmol/rat i.c.v.
Fig. 1. Inhibitory effect of DAGO (38 pmol), β-endorphin (10 pmol) and endomorphin-2 (0.1 pmol)
on the formation of ethanol-induced mucosal lesions in male Wistar rats given i.c.v. 10 min before
the ethanol challenge in a volume of 10 μl. The rats were pretreated i.c.v. either with 6-hydroxydopamine
(6-OHDA) (600 nmol/rat) or vehicle 6 days prior to experiments. Each column represents mean ±
SEM. For statistical analysis ANOVA was used, followed by Newman-Keuls post hoc test. n = 5, ** p <
0.01, *** p < 0.005 compared to the control (saline-treated) group; # p < 0.05, ### p < 0.005 compared
to the respective drug-treated group.
Noradrenaline concentration
(pg/mg tissue)
2,000
1,800
*
1,600
1,400
1,200
1,000
0
Vehiculum
6-OHDA
600 nmol/rat i.c.v.
Neuropeptides, Centrally Induced Gastroprotection
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Fig. 2. Effect of 6-hydroxydopamine (6-OHDA) (600 nmol/rat i.c.v.) on noradrenaline concentration
of nucleus of the solitary tract measured by HPLC on male Wistar rat. The rats were given i.c.v. either
6-OH dopamine or vehicle 6 days before the measurement. Each column represents mean ± SEM.
For statistical analysis ANOVA was used, followed by Newman-Keuls post-hoc test. n = 4, * p < 0.05
compared to the vehicle-treated control group.
potent gastroprotective component of the hormonal response to stress [30]. However,
pro-opiomelanocortin (POMC) is the common precursor for the stress hormone
ACTH and the opioid peptide β-endorphin, and this association implies a close linkage between the stress axis and opioid system. Consequently, β-endorphin can be
additional gastroprotective component of central response to stress.
Conclusion
The central nervous system has a profound role in regulation of gastric mucosal integrity. Different neuropeptides were shown to protect the gastric mucosa in experimental ulcer models. The effective gastroprotective doses of most of the neuropeptides
are in the picomolar dose range, endomorphin-1 and endomorphin-2, β-endorphin,
proved to be effective even in femtomole doses. Dorsal vagal complex and vagal
efferents have basic role in conveying the centrally initiated effect to the periphery. However, the potential role of sympathetic nervous system in centrally induced
mucosal protection has also been raised and further research is needed to reveal its
role in the central regulation of gastric mucosal defense.
Ackowledgements
The authors wish to thank Professor Marton Fekete for his valuable help in determination of noradrenaline concentration. The authors acknowledge financial support from the National
Development Agency (TAMOP-4.2.1/B-09/1/KMR-2010).
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Neuropeptides, Centrally Induced Gastroprotection
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Dr. Klara Gyires
Department of Pharmacology and Pharmacotherapy
Faculty of Medicine, Semmelweis University
Nagyvárad tér 4
1089 Budapest (Hungary)
Tel. +36 1 210 4416, E-Mail gyirkla@net.sote.hu
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