Article

A gut feeling about GABA: focus on GABA(B) receptors

Alimentary Pharmabiotic Centre and Department of Pharmacology and Therapeutics, University College Cork Cork, Ireland.
Frontiers in Pharmacology (Impact Factor: 3.8). 10/2010; 1:124. DOI: 10.3389/fphar.2010.00124
Source: PubMed
ABSTRACT
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABA(A) or metabotropic GABA(B). The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABA(B) receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABA(B) receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABA(B) receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABA(B) receptor agonists, positive allosteric modulators of the GABA(B) receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABA(B) receptors within the GI tract.

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Review ARticle
published: 04 October 2010
doi: 10.3389/fphar.2010.00124
A gut feeling about GABA: focus on GABA
B
receptors
Niall P. Hyland* and John F. Cryan*
Alimentary Pharmabiotic Centre and Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence
GABA-mediated neurotransmission regulates many physiological functions, including those
in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric
nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an
endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which
are either ionotropic GABA
A
or metabotropic GABA
B
. The latter which respond to the agonist
baclofen have been least characterized, however accumulating data suggest that they play a
key role in GI function in health and disease. Like GABA, GABA
B
receptors have been detected
throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as
well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor
is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric
acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful
colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be
determined, suggest GABA
B
receptors inhibit GI carcinogenesis and tumor growth. Therefore,
the diversity of GI functions regulated by GABA
B
receptors makes it a potentially useful target
in the treatment of several GI disorders. In light of the development of novel compounds such
as peripherally acting GABA
B
receptor agonists, positive allosteric modulators of the GABA
B
receptor and GABA producing enteric bacteria, we review and summarize current knowledge
on the function of GABA
B
receptors within the GI tract.
Keywords: GABA
B
, motility, visceral hypersensitivity, secretion, baclofen, allosteric modulator, agonist
transcribed from the Gabbr1
gene, GABA
B1a
and GABA
B1b
, which
are conserved in different species including humans (Kaupmann
et al., 1997; Bischoff et al., 1999; Fritschy et al., 1999). The human
GABA
B1
gene encodes a third isoform, GABA
B1c
, a functional role for
which has yet to be determined, although it may play a role in the
developing human brain (Calver et al., 2002). In the human GI tract
there appears to be a similar expression pattern for both GABA
B1a
and GABA
B1b
splice variants, with little or no expression of GABA
B1c
(Calver et al., 2000). The GABA
B1a
and GABA
B1b
isoforms differ by
the insertion of a pair of tandem “Sushi” domains, which are poten-
tially involved in protein–protein interactions, in the N-terminus
of GABA
B1a
, and differentiate this isoform from GABA
B1b
(Calver
et al., 2002). In the GABA
B1b
subtype, the N-terminal extracellular
domain is the ligand binding domain and differs from the GABA
B1a
splice variant at the N-terminus by the presence of a tandem pair
of CP modules, while the GABA
B1c
splice variant differs in the fifth
transmembrane region and the second extracellular loop by an
additional 31 amino acids (Blein et al., 2000). Human GABA
B1c
is
similar to GABA
B1a
yet lacks one “Sushi” repeat because the splice
machinery skips exon 4 and its expression pattern parallels that
of GABA
B1a
(Bettler et al., 2003). It appears at least in some brain
regions that GABA
B1a
and GABA
B1b
can participate, through het-
erodimerization with GABA
B2
, in the formation of both pre- and
post-synaptic receptors. Similar heterodimerization has also been
postulated to occur in the GI tract between GABA
B1
and GABA
B2
(Kawakami et al., 2004) and is further supported by recent immu-
nohistochemical data obtained for both subunits in the upper GI
tract (Torashima et al., 2009).
IntroductIon
γ-Aminobutyric acid (GABA) is the main inhibitory neurotrans-
mitter in the body and hence GABA-mediated neurotransmission
regulates many physiological functions, including those in the
gastrointestinal (GI) tract. There are two major classes of GABA
receptors and these are classified as either ionotropic GABA
A
(including GABA
C
) receptors or metabotropic GABA
B
receptors
(Barnard et al., 1998; Bormann, 2000; Bowery et al., 2002; Cryan
and Kaupmann, 2005). It is now over 30 years since these latter
receptors were first pharmacologically characterized, and baclofen
was identified as a selective GABA
B
receptor agonist. GABA
B
recep-
tors modulate neurotransmitter release presynaptically by depress-
ing Ca
2+
influx via voltage-activated Ca
2+
channels (Bowery et al.,
2002; Figure 1) while postsynaptic GABA
B
receptors couple mainly
to inwardly rectifying K
+
channels (Luscher et al., 1997) and medi-
ate slow inhibitory postsynaptic potentials (Bowery et al., 2002;
Figure 1). As well as expression in the brain, GABA
B
receptors are
also abundantly expressed in the GI tract, therefore in this review
we will summarize current knowledge on the function of GABA
B
receptors in the GI tract.
GABA
B
receptor proteIns
The first GABA
B
receptor cDNAs were isolated only in 1997
(Kaupmann et al., 1997). The identification of a second GABA
B
receptor protein soon after led to the discovery that native GABA
B
receptors are heterodimers composed of two subunits, GABA
B1
and
GABA
B2
(reviewed in Calver et al., 2002; Bettler et al., 2004). In the
brain two predominant, differentially expressed splice variants are
Edited by:
Pamela J. Hornby, Johnson & Johnson,
USA
Reviewed by:
Jack Grider, Virginia Commonwealth
University, USA
Anders Lehmann, AstraZeneca R&D
Mölndal, Sweden
Vicente Martinez, Autonomous
University of Barcelona, Spain
Amanda J. Page, Royal Adelaide
Hospital, Australia
*Correspondence:
Niall P. Hyland and John F. Cryan,
Alimentary Pharmabiotic Centre and
Department of Pharmacology and
Therapeutics, University College Cork,
Cork, Ireland.
e-mail: n.hyland@ucc.ie; j.cryan@ucc.ie
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Frontiers in Pharmacology | Gastrointestinal Pharmacology October 2010 | Volume 1 | Article 124 | 2
Hyland and Cryan GABA
B
receptors and gastrointestinal function
these receptor isoforms in physiological processes (Jacobson et al.,
2006, 2007; Vigot et al., 2006), however, such studies have yet to be
extended into the GI tract.
LocALIzAtIon of GABA And GABA
B
receptors In the
GAstroIntestInAL trAct
γ-Aminobutyric acid is located throughout the GI tract and has
been localized in enteric nerves as well as in endocrine-like cells
implicating GABA as both a neurotransmitter and an endocrine
mediator in the GI tract. The primary synthesis pathway for enteric
GABA is catalyzed by l-glutamate decarboxylase (GAD; Figure 1)
using the substrate glutamate, and has been localized in both
Dogiel type I and Dogiel type II enteric neurons (for a review see
Krantis, 2000). High affinity plasma membrane GABA transporters
(GAT) are also present in the rat GI tract and have been localized
to both enteric glia (GAT2) and myenteric neurons (GAT3) of the
duodenum, ileum, and colon (Fletcher et al., 2002). In the enteric
nervous system (ENS) approximately 5–8% of myenteric neurons,
which largely regulate GI motility, contain GABA, and in the colon
it predominantly co-localizes with the inhibitory neurotransmit-
ter somatostatin, but also to a lesser extent with enkephalins and
nitric oxide (Krantis, 2000). GABA has also been implicated in the
regulation of intestinal fluid and electrolyte transport by virtue of its
presence in submucosal nerve cell bodies and mucosal nerve fibers
(Krantis, 2000). Therefore, it is not surprising that GABA plays a
multifunctional role in the regulation of GI activity. In addition to
the ENS and endocrine-like sources of GABA, newer endeavors have
adapted Bifidobacteria, found in the intestines of breast-fed children
and healthy adults, to increase GABA production by genetically
increasing GAD activity (Park et al., 2005), and GABA-producing
bacteria have been exploited in the production of GABA-containing
functional foods such as fermented goats milk (Minervini et al.,
2009). Genetically exploiting commensal bacteria to elevate intes-
tinal GABA production allows for local delivery of GABA to the GI
tract and may therefore be of some therapeutic use in regulating
epithelial proliferation (see GABA
B
Receptors and Gastrointestinal
Carcinogenesis) or may directly alter intestinal secretory activity.
Although the current literature would suggest that GABA would
need to access the enteric plexi to exert an effect on the later (see
GABA
B
Receptor Modulation of Intestinal Electrolyte Transport).
Nakajima et al. (1996) demonstrated using an antibody generated
against amino-terminal blocked baclofen, GABA
B
receptor immu-
noreactivity in the rat ENS, muscle and epithelial layers. The 80-kDa
antigen against which the antibody was raised was subsequently
demonstrated to bind GABA and baclofen, but not the GABA
A
antagonist, bicuculline (Nakayasu et al., 1993). Our own studies
in mouse intestine, using a different GABA
B1
receptor antibody
(Ab25; Engle et al., 2006) corroborated the findings of Nakajima
et al. (1996) with respect to localization of GABA
B
receptors on both
submucosal and myenteric neurons in the ENS, however we did not
detect any mucosal staining in this species (Casanova et al., 2009).
In the rat mucosal epithelium, GABA
B
receptor positive cells were
observed along the length of the GI tract from the gastric body to
the colon, decreasing in number in the oral to anal direction, on cells
that were morphologically similar to enteroendocrine cells. Both
gastric and intestinal regions displayed mucosal GABA
B
immuno-
reacticity, however gastric GABA
B
-positive cells tended to contain
Partial cDNAs corresponding to putative GABA
B2
splice variants
have also been isolated (Clark et al., 2000). However, investigation
of the Gpr51 (Gabbr2) gene structure did not provide evidence
that these cDNAs correspond to additional GABA
B2
splice variants
(Martin et al., 2001). Furthermore, the absence of an expression
profile for GABA
B2a
, GABA
B2b
, and GABA
B2c
in the human GI tract
would suggest such splice variants do not play a significant role
in GI function (Calver et al., 2000). Therefore, it seems likely that
in the brain two major populations of heteromeric GABA
B
recep-
tors exist, GABA
B1a,2
and GABA
B1b,2
. The behavioral phenotypes of
mice with targeted deletions of either the GABA
B1
(Prosser et al.,
2001; Schuler et al., 2001; Mombereau et al., 2004) or the GABA
B2
subunits (Gassmann et al., 2004; Mombereau et al., 2005) are
similar and corroborate the in vitro experiments demonstrating
that functional GABA
B
receptor responses are dependent on the
heterodimerization of GABA
B1
and GABA
B2
subunits. Additionally,
GABA-mediated inhibition of GI motility appears to be dependant
on the GABA
B1
receptor subunit (Sanger et al., 2002). The more
recent development of mice lacking both the GABA
B1a
and GABA
B1b
receptor splice variants have been generated (Vigot et al., 2006)
and are proving to be very useful in understanding the role of
FIGURE 1 | (1) Synthesis of γ-aminobutyric acid (GABA) from glutamine/
glutamate (catalyzed by l-glutamate decarboxylase (GAD); (2) transport
and storage of GABA; (3) release of GABA by exocytosis; (4) binding to
GABA
B
receptors and subsequent downstream effects mediated via a G
protein and/or cAMP to K
+
and Ca
2+
channels; (5) binding to presynaptic
receptors; (6) reuptake in presynaptic terminal and uptake by glia; (7)
transamination of GABA to α-ketoglutarate (catalyzed by GABA
transaminase, GABA-T), thereby regenerating glutamate and glutamine;
glial glutamine then re-enters the neuron.
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Hyland and Cryan GABA
B
receptors and gastrointestinal function
either region of the human GI tract (Calver et al., 2000). Despite
the initial findings of Calver et al. (2000) subsequent studies have
identified GABA
B2
message in the human lower esophageal sphinc-
ter (LES), cardia and corpus (Torashima et al., 2009) as well as in
dog intestine (Kawakami et al., 2004). Furthermore, immunohisto-
chemical analysis identified GABA
B2
protein on myenteric neurons
in human LES and gastric corpus (Torashima et al., 2009).
GABA
B
receptors And GAstroIntestInAL functIon
GABA
B
-Induced synthesIs And reLeAse of enterIc
neurotrAnsmItters And entorocromAffIn ceLL-derIved
serotonIn
Microdialysis sampling of myenteric plexus neurotransmitter release
demonstrated a significant inhibitory effect of the GABA
B
receptor
agonist, baclofen on canine intestinal acetylcholine (ACh) release
and this was sensitive to GABA
B
receptor antagonism (Kawakami
et al., 2004). Of particular note, in this species at least, was the
sensitivity of ACh release (and motility) to the GABA
B
receptor
antagonist alone (Kawakami et al., 2004). Therefore, in the canine
ileum it would appear that GABA
B
receptor activation is inhibitory
and that GABA via GABA
B
receptors tonically inhibits excitatory
ACh release. In contrast, release of the inhibitory neurotransmitter,
vasoactive intestinal polypeptide from rat colon was insensitive to
inhibition by the GABA
B
receptor antagonist, phaclofen (Grider
and Makhlouf, 1992). Similarly, in guinea-pig ileum the produc-
tion of electrically induced citrulline, as a marker for nitric oxide
synthase activity, was insensitive to GABA
B
receptor modulation
with baclofen, but was reduced by the GABA
A
agonist, muscimol
(Hebeiss and Kilbinger, 1999). Therefore, with the caveat of spe-
cies differences, it would appear that GABA
B
receptors exert an
inhibitory effect on release of ACh, without any significant effect
on inhibitory neurotransmitter release or synthesis.
Both GABA
A
and GABA
B
receptors have also been shown to reg-
ulate the release of enterochromaffin cell-derived serotonin from
guinea-pig small intestine, although they appear to have opposing
effects (Schworer et al., 1989). Baclofen-induced, GABA
B
-driven,
inhibition of serotonin release occurs via a tetrodotoxin (TTX) insen-
sitive, non-neural pathway while GABA
A
receptor activation causes
a predominant TTX-sensitive, muscarinic receptor-driven release
of serotonin (Schworer et al., 1989). Therefore, the potential exists
for GABA
B
receptors to indirectly regulate ENS activity via release
of enteroendocrine-cell derived mediators such as serotonin.
GABA
B
receptor moduLAtIon of IntestInAL motILIty
γ-Aminobutyric acid, and as such GABA receptor-mediated effects
on GI motility are dependant on an intact ENS as isolated rat smooth
muscle cells are unresponsive to addition of GABA (Grider and
Makhlouf, 1992). Both electrically induced ileal twitch responses
and spontaneous colonic smooth muscle contraction (cholinergic
in nature) are sensitive to inhibition by baclofen in the guinea-pig
(Ong and Kerr, 1982; Allan and Dickenson, 1986; Minocha and
Galligan, 1993; Table 1). In vitro data suggest that this GABA
B
-
mediated inhibitory effect is countered by GABA
A
receptors, as
GABA
A
receptor activation caused a right-ward shift in the ED
50
for
baclofen on the ileal twitch response, and this was recovered to some
extent in the presence of the GABA
A
receptor antagonist, bicuculline
(Allan and Dickenson, 1986). In addition to which complex GABA
B
somatostatin, in contrast to duodenal GABA
B
positive cells which
stained positively for serotonin (Nakajima et al., 1996). Therefore,
the functional effects of GABA
B
receptors are likely to differ along
the GI tract, and are likely to be dependant on its colocalization with
prominent enteroendocrine cell mediators such as somatostatin and
serotonin. Neural GABA
B
-positive fibers were observed in the mus-
cle layers of the rat GI tract, and both plexi of the ENS (Nakajima
et al., 1996). In the myenteric plexus at least 50% of GABA
B
positive
neurons display NADPH-diaphorase activity (Nakajima et al., 1996)
suggesting that GABA
B
receptors may directly modulate inhibitory,
nitric oxide-driven neurotransmission. By taking advantage of newly
developed transgenic mice expressing GABA
B1a
and GABA
B1b
subu-
nits fused to the enhanced green fluorescence protein (eGFP) we also
immunohistochemically localized the GABA
B1
receptor subunit to
both myenteric and submucosal neurons in mouse colon and ileum
(Figure 2). Similar to our studies with an anti-GABA
B1
antibody,
we did not detect any enteroendocrine-like staining for the GABA
B
receptor subtype in this species (Casanova et al., 2009).
Analysis of GABA
B
receptor subunit expression has been exam-
ined in human small intestine and stomach (Calver et al., 2000),
rat small and large intestine (Castelli et al., 1999) as well as dog
intestine (Kawakami et al., 2004). In the human GI tract GABA
B1
and GABA
B2
subunits are differentially expressed (Calver et al.,
2000) with the GABA
B1
receptor subunit, and its splice variants
GABA
B1a
and GABA
B1b
predominating. GABA
B2
on the other hand,
irrespective of the splice variant examined, was undetectable in
FIGURE 2 | Fluorescence immunohistochemistry using anti-eGFP
antibodies revealed GABA
B1
-eGFP localization in the submucosal
(arrowheads) and myenteric plexus (arrows) of GB1
/
mice modified to
express GABA
B1a
and GABA
B1b
subunits fused to the enhanced green
fluorescence protein (eGFP) using a modified bacterial artificial
chromosome containing the GABA
B1
gene (BAC
+/+
; Casanova et al., 2009)
in mouse ileum (A) and colon (B), GABA
B1
-eGFP was not detected in either
the epithelial layer or enteroendocrine cells of GB1
/
, BAC
+/+
ileum and colon
(A,B). Whole mount preparations of ileum (C) and colon (D) revealed a
cytoplasmic, non-nuclear, distribution of GABA
B1
-eGFP in enteric neurons of
GB1
/
, BAC
+/+
mice. Scale bars = 100 μm. LM, longitudinal muscle; CM,
circular muscle; Mu, mucosa. Adapted from Casanova et al. (2009).
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Hyland and Cryan GABA
B
receptors and gastrointestinal function
of a distended balloon along rabbit colonic preparations was sig-
nificantly reduced by GABA
B
receptor activation with baclofen,
consistent with an inhibitory effect of this receptor on excitatory
neurotransmission (Tonini et al., 1989; Table 1). In the same spe-
cies, baclofen had a minor inhibitory effect on colonic longitudinal
muscle tone but a more significant inhibitory effect on TTX- and
hyoscine-sensitive electrically stimulated responses, suggesting that
the inhibitory effects of the GABA
B
agonist on colonic activity in the
rabbit is dependant on cholinergic neurotransmission (Tonini et al.,
1989; Table 1). Consistent with modulation of cholinergic enteric
nerves, baclofen decreases both GABA
B
receptor-induced relaxation
of guinea-pig ileal (Giotti et al., 1983) and colonic (Giotti et al., 1985)
longitudinal muscle via a TTX-sensitive, cholinergic pathway and
in vivo inhibited physostigmine-induced colonic tone (Giotti et al.,
1985; Table 1). GABA receptor-induced relaxation appears to be
mediated predominantly via GABA
B
receptors in guinea-pig colon,
as less than 10% of the GABA-induced relaxant effect is sensitive
receptor-dependant signaling pathways, in the guinea-pig ileum at
least, have been identified and involve GABA
B
receptor-mediated
inhibition of somatostatin-sensitive cholecystokinin-induced con-
traction (Roberts et al., 1993; Table 1).
In the human GI tract spontaneous activity of jejunal lon-
gitudinal muscle is sensitive to inhibition by both GABA and
baclofen. However, spontaneous colonic activity was insensitive
to GABAergic modulation (Gentilini et al., 1992) suggesting that
GABA
B
receptor-mediated inhibition predominates in the small
intestine of humans. However, in other species GABA
B
receptors
have been demonstrated to alter colonic motor activity. For example,
desensitization of GABA
B
receptors with baclofen, thereby relieving
GABA
B
-induced effects on motility, resulted in decreased colonic
fecal pellet output in the guinea pig (Ong and Kerr, 1982; Table 1),
potentially due to dysregulation of cholinergic activity and peri-
stalsis as suggested by the authors, or a disinhibition of inhibitory
activity. In contrast to the guinea-pig colon, the propulsive velocity
Table 1 | Summary of GABA
B
receptor-induced effects on gastrointestinal motility.
Region Species Baclofen induced-effect Reference
Duodenum/jejunum Human TTX sensitive inhibition of spontaneous Gentilini et al. (1992)
and DMPP-induced contraction
Rat Reduction in electrically evoked Krantis and Harding (1987)
cholinergic contraction
Disruption of migrating motor Fargeas et al. (1988)
complex activity (i.v. administration)
Atropine-sensitive increase in
migrating motor complex activity (i.c.v. administration)
Ileum Guinea-pig Decrease in electrically evoked Ong and Kerr (1982) and
(cholinergic) twitch response Marcoli et al. (2000)
Relaxation (all levels of the intestine) Ong and Kerr (1987)
Inhibition of somatostatin inhibitory activity Roberts et al. (1993)
on cholocystokinin-induced contraction (cholinergic)
TTX- and hyoscine-sensitive relaxation (basal) and Giotti et al. (1983)
hyoscine-sensitive relaxation following histamine
and prostaglandin F
2α
stimulation
Inhibition of electrically stimulated NO-mediated relaxation Kilbinger et al. (1999)
Mouse Inhibition of electrically evoked contraction (GABA
B1
+/+) Sanger et al. (2002)
Loss of baclofen-induced relaxation (GABA
B1
/)
Cat Contraction of longitudinal muscle (distal and terminal ileum; Pencheva et al. (1999)
modest if any sensitivity to atropine and TTX) and
no effect on circular muscle activity
No effect (proximal ileum) on longitudinal or circular muscle activity
Intestine Dog Reduction of circular muscle motor activity Kawakami et al. (2004)
coupled with a decrease in ACh release (intra arterial administration)
Colon Human No effect Gentilini et al. (1992)
Guinea-pig Decrease in fecal pellet expulsion and TTX-sensitive relaxation Ong and Kerr (1982)
Decrease in basal and physostigmine-induced tone (i.v. administration) Giotti et al. (1985)
TTX and scopolamine-sensitive relaxation Giotti et al. (1985) and
Minocha and Galligan (1993)
Rat Increase in electrically evoked cholinergic and non-cholinergic Bayer et al. (2003)
circular muscle contraction that is sensitive to nicotinic receptor blockade
Rabbit Modest decrease in resting tone and inhibition of electrically-induced Tonini et al. (1989)
(cholinergic) contraction. Inhibition of NANC neurotransmission and decreased transit
ACh, acetylcholine; DMPP, dimethylphenylpiperazinium; i.v. intravenous; i.c.v. intracerbroventricular; NANC, non-adrenergic non-cholinergic; NO, nitric oxide; TTX,
tetrodotoxin. Unless otherwise noted in italicize, all drug additions were to in vitro preparations.
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Hyland and Cryan GABA
B
receptors and gastrointestinal function
the inhibitory effect of GABA on afferent activity, although this
inhibitory effect varied dependent on the sensitivity of the fibers
to mucosal, tension or tension-mucosal stimulation, in addition
to which Ca
2+
- and K
+
-independent pathways were also identified
(Page et al., 2006). In addition to vagal afferents, GABA
B
recep-
tors also regulate spinal afferent signaling (Hara et al., 1990,
1999; Sengupta et al., 2002). Intrathecal injection of baclofen
significantly reduced the threshold response to colorectal dis-
tension (CRD) in a dose-dependant manner (Hara et al., 1999).
Furthermore, when co-administered with morphine, the anti-
nociceptive effect of the later was potentiated, indicative of a
GABA
B
-opiod receptor interaction, which the authors suggest
may involve synergistic activation of cAMP and potentiation of
the anti-nociceptive effects of both GABA and morphine (Hara
et al., 1999). A similar potentiation of the baclofen-induced effect
on visceral pain was also observed with the Ca
2+
channel blocker,
diltiazem (Hara et al., 2004). In addition to acting synergistically
with morphine and diltiazem, both studies also demonstrated
that intrathecal administration of baclofen alone was sufficient
to reduce the visceral pain response to CRD (Hara et al., 1999,
2004). These functional data are consistent with subsequent find-
ings describing baclofen-sensitive electrical activity of S
1
dorsal
roots following pelvic nerve stimulation during CRD (Sengupta
et al., 2002).
Moreover, systemic intravenous (i.v.) administration of baclofen
to rats also significantly reduced the visceral pain response, sug-
gesting the GABA
B
agonist can potentially exert its anti-nociceptive
effects at sites outside the central nervous system, including in the
GI tract (Brusberg et al., 2009). The same authors also demon-
strated that the positive allosteric modulator of the GABA
B
recep-
tor, CGP7930 also displayed efficacy in reducing CRD-induced
effects on the visceromotor response, blood pressure, and heart
rate following i.v. administration (Brusberg et al., 2009). However,
the efficacy of CGP7930 was less than that of baclofen (Brusberg
et al., 2009), potentially as its mechanism of action as an allos-
teric modulator is dependant on the levels of endogenous GABA
or GABA tone. In a similar manner to baclofen, CGP7930 does
not appear to alter colonic compliance (Brusberg et al., 2009),
suggesting the anti-nociceptive effect of CGP7930 is not due to
increased accommodation, as a result of muscle relaxation, of the
distension stimulus.
In addition to decreasing CRD-induced pain responses,
baclofen also alters gut to brain signaling following periph-
eral colonic inflammation (Lu and Westlund, 2001). Mustard
oil- induced colonic inflammation significantly enhanced spinal
cord expression of the early gene product Fos, and this response
was sensitive to inhibition by baclofen (Lu and Westlund, 2001),
suggesting a dampening of afferent signaling from the periphery
to the central nervous system. Additionally, baclofen pretreatment
per se, as well as in the presence of mustard oil, concomitantly
increased activity in the rostral nucleus tractus solitarius sug-
gesting that activation of descending anti-nociceptive autonomic
pathways or an inhibition of inhibitory activity may also occur,
resulting in an enhancement of Fos activity (Lu and Westlund,
2001). Therefore, GABA
B
receptor agonists have the potential to
exert a dual effect in the GI tract in response to noxious physical
or chemical stimuli by decreasing afferent signaling and enhanc-
ing anti-nociceptive outflow.
to GABA
A
receptor blockade (Giotti et al., 1985). However, there is
also evidence for GABA
A
receptor-mediated activation of inhibi-
tory pathways in guinea-pig colon (Minocha and Galligan, 1993)
which one would expect to potentiate GABA
B
-mediated relaxation.
Non-adrenergic non-cholinergic inhibitory responses also display
sensitivity to GABA
B
receptor activation in the rabbit (Tonini et al.,
1989; Table 1), indicative of a co-ordinated regulatory role for
GABA
B
receptors in the modulation of peristalsis in this species.
The availability of GABA
B
subunit receptor deficient mice has
led to further characterization of GABA
B
receptor-mediated effects
in the GI tract (Sanger et al., 2002). Baclofen-induced inhibitory
responses were observed in wildtype mouse intestine following
electrical stimulation, but were absent in GABA
B1
subunit deficient
animals (Sanger et al., 2002). This unresponsiveness to baclofen does
not appear to be due to an overt dysregulation of ileal function in
GABA
B1
mutant mice as these animals respond in a similar manner
as wildtype animals to both electrical and cholinergic stimulation
(Sanger et al., 2002; Table 1). Therefore, the functional dependence
of GABA
B
receptors in the mouse is dependant on the GABA
B1
subu-
nit, and this finding is consistent with the preferential expression
of this subunit in the GI tract of several species, including humans
(Castelli et al., 1999; Calver et al., 2000; Kawakami et al., 2004).
As well as having a peripheral site of action, GABA can exert
effects on GI motility via central mechanisms (Fargeas et al., 1988).
In unanesthetized rats intracerebroventricular administration of
baclofen had a stimulatory effect on GABA
B
receptor- and atropine-
sensitive migrating myoelectric complexes (MMC) (Fargeas et al.,
1988; Table 1). While seemingly in disagreement with in vitro data,
or data from anesthetized animals, which point toward a peripheral
inhibitory effect for GABA
B
receptors in the GI tract, the authors
suggest that this enhancement of MMC activity may represent
baclofen-induced adaptation of vagal efferent activity.
GABA
B
receptor moduLAtIon of IntestInAL eLectroLyte
trAnsport
Despite localization of GABA
B
receptors in the submucosal plexus
of rat (Nakajima et al., 1996) and mouse (GABA
B1
; Casanova et al.,
2009) intestine, they do not appear to be involved in the regula-
tion of electrolyte transport. In guinea-pig intestine, only GABA
A
receptor activation, but not baclofen, mimicked GABA-induced
elevations in short-circuit current (MacNaughton et al., 1996). A
similar bias toward GABA
A
receptor-mediated modulation of chlo-
ride ion-dependant secretion was also observed in rat small intestine
(Hardcastle et al., 1991). However, in this species the GABA-induced
effect was dependent on the presence of intact myenteric neurons,
suggesting a myenteric reflex is involved in initiating the GABA-
induced secretory response (Hardcastle et al., 1991). However, given
the paucity of data in this area it is difficult to draw a firm conclusion
on the role of GABA
B
receptor modulation of intestinal ion transport
which may vary among intestinal regions and across species.
GABA
B
receptors And GAstroIntestInAL Afferent sIGnALInG
And nocIceptIon
Vagal afferent fibers display sensitivity to baclofen and this
response is, as expected, sensitive to GABA
B
receptor antago-
nism (Page and Blackshaw, 1999). Further investigation of this
vagal afferent pathway elucidated GABA
B
receptor-mediated
opening of K
+
, and closing of Ca
2+
channels as contributing to
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Frontiers in Pharmacology | Gastrointestinal Pharmacology October 2010 | Volume 1 | Article 124 | 6
Hyland and Cryan GABA
B
receptors and gastrointestinal function
translational relevance, being the only case of the use of GABA
B
receptors as a clinical target (as recently reviewed by Lehmann,
2009; Lehmann et al., 2010). In pre-clinical studies, intravenous
and intragastric administration of baclofen displayed almost equal
potencies with respect to inhibition of TLESRs in the dog, despite a
concomitant increase in gastric pressure, and these effects were sen-
sitive (to some extent) to GABA
B
receptor antagonism and absent
when the S enantiomer of baclofen was used (Lehmann et al., 1999).
Similar inhibition of TLESRs by baclofen was observed in ferrets
(Blackshaw et al., 1999), and the site of action for the GABA
B
-
mediated effect on TLESR in this species was later demonstrated
to involve inhibition of vagal motor output, via GABA
B
(GBAB
B1
)
receptors (McDermott et al., 2001), and thought to involve sub-
sequent inhibition of non-adrenergic non-cholinergic activity.
However, inhibition of mechano-sensitive gastric vagal afferents
and their central synaptic connections with brain stem neurons
must also be considered as a site of action for GABA
B
receptor
agonists in the treatment of GERD. In parallel clinical trials, con-
ducted in and around the same period as pre-clinical studies, data
demonstrated that baclofen increased lower esophageal pressure
and decreased TLESRs and the number of reflux episodes in healthy
human subjects (Lidums et al., 2000). A later study conducted in
patients suffering from GERD, similarly demonstrated a signifi-
cant effect of orally administered baclofen on esophageal pH and
on the incidence of reflux episodes and TLESRs, however in this
particular study patients did not report any improvement in reflux
symptoms (van Herwaarden et al., 2002). Nonetheless, a subsequent
study indicated that 4 week treatment with baclofen significantly
decreased the intensity of a number of symptoms associated with
reflux, including fasting and post prandial epigastric pain, day- and
night-time heartburn and regurgitation (Ciccaglione and Marzio,
2003). Despite its efficacy in relieving GERD symptoms, one of the
common features associated with baclofen administration in GERD
patients is the development of centrally mediated side-effects, with
over 80% of baclofen-treated patients reporting neurological events
such as dizziness (van Herwaarden et al., 2002). In order to over-
come such central side-effects a number of GABA
B
receptor agonists
have been developed and tested for efficacy in reducing TLESRs,
these include the GABA
B
agonists AZD9343 (Beaumont et al.,
2009), AZD3355 (lesogaberan; Boeckxstaens et al., 2010a,b) and
a prodrug of the R enantiomer of baclofen, XP19986 (arbaclofen
placarbil; Gerson et al., 2010). The pre-clinical data for AZD9343
favored a decreased side-effect profile as its pharmacology suggested
the GABA
B
agonist did not readily cross the blood brain barrier
and was sequestered intracellularly via a GABA-carrier independent
mechanism (Lehmann et al., 2008). Although AZD9343 reduced
the number of TLESRs in healthy volunteers, significant side-effects
unfortunately remained and included drowsiness and paresthesia
(Beaumont et al., 2009). However, other side effects such as the
incidence of dizziness in AZD9343-treated subjects were less than
those reported in the baclofen-treated group (Beaumont et al.,
2009). Of most promise currently in terms of efficacy in treating
the symptoms of GERD and having a reduced side-effect profile is
lesogaberan. Its pharmacology differs from that of AZD9343 in that
lesogaberan displays affinity for GABA carriers, thereby reducing
GABA
B
-mediated central side effects (Lehmann et al., 2009). Initial
trials with lesogaberan in healthy male subjects were positive, with
GABA
B
receptor-medIAted reGuLAtIon of GAstrIc motILIty,
emptyInG, And AcId secretIon
Baclofen exerts a vagus nerve-dependant dual effect on gastric
motility that involves an increase in gastric pressure as a result of
an inhibition of non-adrenergic non-cholinergic inhibitory neu-
rons in the gastric corpus, as well as an atropine-sensitive stimu-
lation of rhythmic contractions in both the corpus and antrum
(Andrews et al., 1987). Moreover, independent of innervation by
the central nervous system, peripheral GABA
B
receptor activation
induces TTX- and atropine-sensitive gastric contractility in vitro
(Rotondo et al., 2010), suggesting that baclofen locally increases
gastric tone through activation of intrinsic cholinergic neurons. Not
unexpectedly then, GABA
B
receptors have been shown to regulate
gastric emptying (in mouse; Symonds et al., 2003). However, this
was dependant on the consistency of the diet consumed and on
the dose of baclofen administered (Symonds et al., 2003). Lower
doses significantly increased gastric emptying of a solid meal, but
decreased emptying of a liquid meal at a higher dose (Symonds
et al., 2003). This divergent effect of baclofen reflects the differ-
ent mechanisms that underlie gastric emptying of solid and liquid
meals. In a model of delayed gastric emptying, induced by central
and peripheral administration of dipyrone, intracerebroventricu-
lar baclofen dose-dependently reversed dipyrone-induced gastric
retention (Collares and Vinagre, 2005).
Given the evidence for central and peripheral regulation of
gastric cholinergic neurons by GABA
B
receptors, it is perhaps not
surprising that GABA and GABA
B
receptors might also influence
cholinergic-induced gastric acid secretion. In keeping with such
a hypothesis baclofen, or the GABA mimetic PCP-GABA, induce
an increase in gastric acid secretion beyond that induced by hista-
mine and cholinergic agonism alone (Goto and Debas, 1983). This
effect occurs independently of GABA
A
receptors (Hara et al., 1990;
Yamasaki et al., 1991) and is accompanied by an increase in vagal
cholinergic outflow (Yamasaki et al., 1991). Consistent with such a
vagal-cholinergic pathway, systemic baclofen-induced acid secretion
(and gastric motility) was inhibited by both atropine and vagotomy
(Andrews and Wood, 1986). Similar effects have also been observed
in mice, and are mimicked by the GABA
B
receptor agonist, SKF-
97541 (Piqueras and Martinez, 2004). As predicted by earlier studies
Piqueras and Martinez (2004), demonstrated a vagally mediated
atropine-sensitive regulation of acid secretion in mouse stomach,
however they also demonstrated that GABA
B
receptor-induced acid
secretion was sensitive to neutralization of gastrin and enhanced in
the presence of a somatostatin neutralizing antibody; the former
suggesting that GABAergic induced gastric acid secretion occurs via
a neurohumoral route which is sensitive to feedback inhibition by
the later. Other studies have identified baclofen-induced acid secre-
tion as also been partially dependant on histamine H
2
receptors, and
identified extravagal effects of baclofen on gastric acid secretion in
vagotomized rats (Blandizzi et al., 1992).
GABA
B
receptors As A therApeutIc tArGet In the
GAstroIntestInAL trAct
GABA
B
receptors And trAnsIent Lower esophAGeAL reLAxAtIon
Modulation of transient lower esophageal sphincter relaxation
(TLESR) and the application of GABA
B
agonists in the treat-
ment of gastroesophageal reflux disease (GERD) is of particular
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www.frontiersin.org October 2010 | Volume 1 | Article 124 | 7
Hyland and Cryan GABA
B
receptors and gastrointestinal function
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effects at central GABA
B
receptors, may well overcome the disadvan-
tages associated with traditional GABA
B
agonists. Lesogaberan, like
baclofen, displays efficacy in the treatment of GERD (Boeckxstaens
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B
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et al., 2008). One of which, CGP7930, reduces the visceral pain
response induced by CRD (Brusberg et al., 2009) and may there-
fore be therapeutically useful in the treatment of functional bowel
disorders such as irritable bowel syndrome where visceral pain is
a predominant and debilitating symptom. These modulators offer
advantages over traditional GABA
B
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their actions occur following enhancement of endogenous GABA
release or transmission, thereby limiting the side-effects that are
normally associated with traditional agonist treatment. More novel
strategies for delivering GABA to the GI tract in the form of engi-
neered bacteria, such as GAD transfected Bifidobacterium longum
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AcknowLedGments
The Alimentary Pharmabiotic Centre is a research centre funded by
Science Foundation Ireland (SFI), through the Irish Governments
National Development Plan. The authors and their work were
supported by SFI (grant no.s 02/CE/B124 and 07/CE/B1368).
John F. Cryan is also funded by European Community’s Seventh
Framework Programme; Grant Number: FP7/2007-2013, Grant
Agreement 201714. The authors would like to thank Dr Marcela
Julio-Pieper for contributing to the artwork in this manuscript.
lesogaberan and baclofen decreasing the number of TLESRs and
reflux episodes to a similar extent (Boeckxstaens et al., 2010a). As
predicted by pre-clinical studies, subjects treated with lesogaberan
had a similar side-effect profile to that observed in those treated with
placebo (Boeckxstaens et al., 2010a). Lesogaberan similarly reduced
TLESRs in patients with GERD and no significant differences in the
side-effect profile between placebo and lesogaberan were observed
(Boeckxstaens et al., 2010b). Therefore therapeutically exploiting
affinity for GABA-carriers may prove to be beneficial in reducing
the central side effects associated with baclofen.
GABA
B
receptors And GAstroIntestInAL cArcInoGenesIs
The GABA
B
-induced effects on gastric pH may potentially inhibit
chemically-induced gastric carcinogenesis observed as a decrease
in the incidence and number of gastric tumors (Tatsuta et al.,
1990). However, this remains unproven, and the exact mechanism
underlying the baclofen-induced decrease in proliferation of antral
mucosa has yet to be determined (Tatsuta et al., 1992). In the rat
lower GI tract, the same group also observed a GABA
B
-induced
inhibitory effect on colon tumor growth, but not incidence (Tatsuta
et al., 1992).
summAry And concLusIons
The diversity of GI functions regulated by GABA
B
receptors make
it a potentially useful target in the treatment of several GI disor-
ders, but may also limit its therapeutic application due to off target
side effects, both in the GI tract and centrally. For example GERD
patients and healthy volunteers treated with baclofen reported
adverse effects of a neurological nature that included drowsiness
and dizziness (Lidums et al., 2000; van Herwaarden et al., 2002;
Ciccaglione and Marzio, 2003). However, the development of
peripherally acting compounds such as lesogaberan, which by vir-
tue of its affinity for GABA carriers (Lehmann et al., 2009) limits its
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Conflict of Interest Statement: The
Alimentary Pharmabiotic Centre and
the authors (Niall P. Hyland and John
F. Cryan) receive research support from
GlaxoSmithKline.
Received: 11 July 2010; paper pending
published: 20 August 2010; accepted: 07
September 2010; published online: 04
October 2010.
This article was submitted to Frontiers in
Gastrointestinal Pharmacology, a specialty
of Frontiers in Pharmacology.
Citation: Hyland NP and Cryan JF (2010)
A gut feeling about GABA: focus on GABA
B
receptors. Front. Pharmacol. 1:124. doi:
10.3389/fphar.2010.00124
Copyright © 2010 Hyland and Cryan. This
is an open-access article subject to an exclu-
sive license agreement between the authors
and the Frontiers Research Foundation,
which permits unrestricted use, distribu-
tion, and reproduction in any medium,
provided the original authors and source
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    • "In support of these in vivo findings, in vitro studies have shown that baclofen reduces TLR4-induced release of pro-inflammatory cytokines from primary murine microglia (Kuhn et al., 2004), indicating that cross talk may exist between the GABAergic and TLR systems, with relevance to inflammatory signaling events. GABA B receptors are metabotropic G i /G o -coupled receptors (Padgett and Slesinger, 2010) which are distributed throughout the CNS and periphery (Ong and Kerr, 1990; Hyland and Cryan, 2010). GABA B receptors can function to regulate ion channels (activate K + and inhibit Ca 2+ channels) and cellular signaling (adenylate cyclase, MAPK; Kornau, 2006; Jiang et al., 2012), limit the release of neurotransmitters (GABA, glutamate; Pinard et al., 2010; Gassmann and Bettler, 2012), and dampen depolarisation induced by excitatory neurotransmitters. "
    [Show abstract] [Hide abstract] ABSTRACT: The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including multiple sclerosis (MS), but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR) family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or) TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs) isolated from healthy control individuals and patients with the relapse-remitting (RR) form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS.
    Full-text · Article · Aug 2015 · Frontiers in Cellular Neuroscience
    • "Enteric GABA sources include neurons containing the GABA-synthesizing enzyme (L-glutamate decarboxylase, GAD), the highest activity being reported in the myenteric plexus, and mucosal endocrine-like cells, suggesting a role of GABA as both a neural and endocrine mediator in the GI tract [1] . GABAergic neuronal cells, mainly interneurons, occur both in submucosal and myenteric plexus throughout the GI tract, with a particular representation in the large intestine where they account for 5–8% of the total myenteric neurons [2]. GABA is potentially involved both in secretory and motor GI function, exerting either a stimulatory or inhibitory action on the neuronal activity, via activation of GABA receptors. "
    [Show abstract] [Hide abstract] ABSTRACT: Although an extensive body of literature confirmed γ-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • "For example, in addition to Entries in italics denote drug and disease classes of the same anatomical area enriched in the same community. the expected connections of gamma-aminobutyric acid (GABA) agents with nervous system-related disease classes [50,55,56], the recently recognized function of the GABAergic system in autonomic function [57] and metabolic diseases [58] is captured in our network. Likewise, serotonin agents are linked to neurodegenerative diseases affecting the central nervous system (Figure 3) as well as to autonomic nervous system diseases. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The incomplete understanding of disease causes and drug mechanisms of action often leads to ineffective drug therapies or side effects. Therefore, new approaches are needed to improve treatment decisions and to elucidate molecular mechanisms underlying pathologies and unwanted drug effects. Methods: We present here the first analysis of phenotypically related drug-disease pairs. The phenotypic similarity between 4,869 human diseases and 1,667 drugs was evaluated using an ontology-based semantic similarity approach to compare disease symptoms with drug side effects. We assessed and visualized the enrichment over random of clinical and molecular relationships among drug-disease pairs that share phenotypes using lift plots. To determine the associations between drug and disease classes enriched among phenotypically related pairs we employed a network-based approach combined with Fisher's exact test. Results: We observed that molecularly and clinically related (for example, indication or contraindication) drugs and diseases are likely to share phenotypes. An analysis of the relations between drug mechanisms of action (MoAs) and disease classes among highly similar pairs revealed known and suspected MoA-disease relationships. Interestingly, we found that contraindications associated with high phenotypic similarity often involve diseases that have been reported as side effects of the drug, probably due to common mechanisms. Based on this, we propose a list of 752 precautions or potential contraindications for 486 drugs. Conclusions: Phenotypic similarity between drugs and diseases facilitates the proposal of contraindications and the mechanistic understanding of disease and drug side effects.
    Full-text · Article · Jul 2014 · Genome Medicine
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