THEMES
Pathobiology of Visceral Pain: Molecular Mechanisms and Therapeutic Implications
III. Visceral afferent pathways: a source of new
therapeutic targets for abdominal pain*
Lionel
Buéno,
Jean
Fioramonti, and
Rafael
Garcia-Villar
Institut National de la Recherche Agronomique,
Neuro-Gastroenterology & Nutrition Unit, 31931 Toulouse, France
 |
ABSTRACT |
Visceral pain is the major cause of consulting in
gastroenterology and the principal symptom of functional bowel
disorders. This symptom is often associated with gut hypersensitivity
to distension. The use of animal models has recently permitted the identification of some mediators supposed to play a pivotal role in the
genesis of visceral hypersensitivity. Serotonin, through different
receptor subtypes, as well as kinins and calcitonin gene-related
peptide, are known to be involved, but other putative transmitters
arise and are new potential targets for the development of efficacious
treatments. This themes article addresses both physiological and
preclinical issues of interest for the selection of active new drugs in
regard to the clinical pharmacology of visceral pain.
gut; mediators; hypersensitivity; functional bowel disorders; serotonin; bradykinin; tachykinins; N-methyl-D-aspartate; calcitonin gene-related
peptide
 |
INTRODUCTION |
ABDOMINAL PAIN may result from visceral
organic disease or surgery, but it also represents the major symptom of
functional bowel disorders (FBD) such as non-ulcer dyspepsia or
irritable bowel syndrome (IBS). In contrast to other chronic pain
diseases, visceral pain is often associated with gut motor
abnormalities that generate exaggerated intraluminal pressures.
Clinical observations in IBS patients indicate that motor functional
reflexes are enhanced and associated with a lowering of the
intraluminal pressure generating pain sensations. These observations
are in agreement with electrophysiological data in animals showing
that, under inflammatory conditions, both low- and high-threshold
baroreceptors of the gut wall are activated at lower, normally
ineffective, intraluminal pressures. Compared with somatic nociceptive
signal generation, the presence in the gut wall of silent nociceptors
that can be activated by immune signals also seems to be important in
the genesis of chronic abdominal pain. At the gut level, there are also
specific connections between the immune system and intrinsic and
extrinsic innervation that modulate local immune and functional reactions.
During the past few years, special attention has been paid to the
specific roles of mast cells and cytokines. Both are able to induce
long-term changes in signaling to the brain and play a pivotal role in
the alteration of motor reflexes and barosensitivity associated with
gastrointestinal symptoms. This themes article focuses on current
knowledge of the structures and mediators specifically involved at the
gastrointestinal tract level in experimental situations that attempt to
mimic events in visceral hyperalgesia.
 |
SENSITIZATION OF PRIMARY AFFERENTS VS. DORSAL HORN |
Peripheral sensitization of primary afferent neuron terminals within
the gut results in a decrease in the intensity and/or amplitude of the
stimulus required to initiate their depolarization and in an increase
in the number and/or amplitude of neuronal discharges in response to a
given chemical or mechanical stimulus. This peripheral sensitization is
believed to result from the release of proinflammatory substances at
the site of injury, such as bradykinin, tachykinins, prostaglandins,
serotonin, ATP, and protons (for review, see Refs. 3 and 11). Most of
these mediators are known to be algogenic substances that act directly
on receptors located at sensory nerve terminals to depolarize these
neurons and initiate nociceptive inputs to the spinal cord; they can
also lower the threshold for activation by normally active mechanical and chemical stimuli, and they can activate local immunocytes and/or
other cells, like mast cells or sympathetic varicosities, which in turn
release algogenic substances acting on sensory nerve endings (Fig.
1). Growth factors, such as nerve growth
factor (NGF), are present both in gut tissues and mast cells and are released during mast cell degranulation. These factors are involved in
neuronal plasticity but may also change the distribution of receptors
to algogenic mediators and the threshold of sensitivity to mechanical
and chemical stimuli. In addition, an enhanced expression of sodium
channels has been proposed to explain the hypersensitivity of
peripheral neurons that results from injury (13).

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Fig. 1.
Substances and major local pathways involved in triggering hyperalgesia
to distension within gut. Note that several mediators, such as
substance P, may directly and indirectly influence threshold of
response of afferent fibers to a mechanical stimulus.
8(R),15(S)-diHETE, dihydroeicosatetraenoic acid; NGF, nerve growth
factor; fMLP, formyl-Met-Leu-Phe; C5a, complement 5a; VIP, vasoactive
intestinal peptide; NPY, neuropeptide Y; IL, interleukin; TNF, tumor
necrosis factor, CGRP, calcitonin gene-related peptide.
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The sustained activity of primary afferent fibers that occurs after
peripheral sensitization favors the release of neuromediators, increasing the efficacy of synaptic transmission between primary afferents and dorsal horn neurons, a process, referred to as central sensitization (for review, see Ref. 9), that involves specific pre- and
postsynaptic receptors (Fig. 2). Despite a
different localization in laminae between somatic and visceral
projecting neurons at the dorsal horn, the mechanisms of sensitization
at this level are similar, yet only very few experimental data are available for the gut. The mechanisms that underlie central
sensitization are not fully understood. In vitro and in vivo
pharmacological studies implicate a cooperation between substance P
(SP) and N-methyl-D-aspartate (NMDA)-mediated
events in the development and maintenance of inflammation-induced central sensitization (for review, see Ref. 11). The increased responsiveness of dorsal horn neurons in chronic inflammation is
largely mediated by activated NMDA receptors. This activation of NMDA
receptors depends on protein kinase C activation, particularly of
extracellular signal-regulated kinase phosphorylation
(14). The interaction of SP receptors with protein kinase C induces the
phosphorylation of NMDA receptors, counteracting the magnesium block
and allowing NMDA receptors to operate at a more negative potential
(for review, see Ref. 19). All of these data strongly suggest that SP
and neurokinin (NK)1 receptors are crucial for the
induction of central sensitization in rodents. However, the failure of
NK1 receptor antagonists in clinical trials for pain states
indicates that another receptor may probably fulfill this function in
humans. Obvious candidates in spinal cord are the other tachykinin
receptors, i.e., NK2 and NK3 receptors (see
SPECIFIC MEDIATORS OF GUT
HYPERSENSITIVITY). Increased release of these mediators is concomitantly observed at the periphery in visceral inflammation, but the role of SP in sensitization following colonic inflammation remains controversial.

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Fig. 2.
Mediators identified in spinally projecting visceral afferent neurons
and pre- and postsynaptic receptors involved in transmission of
nociceptive messages at dorsal horn level. SP, substance P; NKA,
neurokinin A; NKB, neurokinin B, NMDA,
N-methyl-D-aspartate; AMPA:
-amino-3-hydroxy-5-methyl-isoxazole-4-propionate;
NK1, NK2, and NK3, neurokinin
receptor types 1, 2, and 3; 5-HT1 and 5-HT3,
serotonin receptor types 1 and 3; SST3, somatostatin receptor type 3.
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It has recently been shown that neurons expressing high-affinity (TrkA)
receptors for NGF participate in the first central relay of
transmission of nociceptive information to supraspinal centers, with an
increased number of TrkA receptors or TrkA-immunoreactive neurons as
demonstrated in chronic pain states (23). The expression of sodium
channels is also enhanced at the spinal cord level in models of
neuropathic or inflammation-induced pain. This increase is rapid,
prolonged, and well correlated with the hyperalgesia (13), but, in
contrast to neuropathic pain, its relevance to inflammation-induced
pain remains to be clinically demonstrated using selective sodium
channel blockers. The expression of vasoactive intestinal peptide and
pituitary adenylate cyclase-activating polypeptide is also altered
during experimental inflammation and neuropathy [chronic constriction
injury (CCI)]-induced chronic pain, suggesting their
involvement at the dorsal horn level. Vasoactive intestinal peptide
overexpression lasts several weeks, whereas the expression of
vasoactive intestinal peptide (VIP)/pituitary adenylate
cyclase-activating polypeptide (PACAP) receptor isoforms 1 and 2 (VPAC1, VPAC2) and PACAP type 1 receptor (PAC1) is differently affected
according to the experimental model and the lamina considered (10).
 |
MODELS OF GUT HYPERALGESIA |
During the past decade, numerous models have been developed, mainly in
rats, to investigate new targets for the treatment of visceral pain.
Most of them are based on the induction of either visceral or somatic
responses to a local mechanical stimulus. Recently, several models of
inflammation-induced or chemically induced pain have been developed to
evaluate spontaneous pain or behavioral changes as markers of pain or
discomfort. According to the multifactorial origin of pain in FBD and
the lowered threshold of pain perception in these patients, local
distension of the upper or lower part of the gut is performed.
Intraluminal or intraparietal administration of irritating agents such
as trinitrobenzenesulfonic acid (TNBS), formalin, or
acetic acid (for review, see Ref. 3) often induces hypersensitivity to
distension. Other models, related to postinfection visceral pain
syndrome, have recently been validated, in which the hypersensitivity
to distension results from the mastocytosis induced by intestinal
parasitism (18), anaphylactic shock, or septic shock (unpublished
observations). Measurements can either be limited to
the determination of the threshold of reaction (first abdominal cramp)
or take into account the intensity of the responses (number of
abdominal cramps, number of identified postures, amplitude of the
cardiovascular reflex response).
 |
SPECIFIC MEDIATORS OF GUT HYPERSENSITIVITY |
So far, no specific mediator has been identified that discriminates
between visceral pain and somatic pain, although some mediators are
more implicated in visceral hyperalgesic states. No mediator appears to
be highly selective for either low- or high-threshold subpopulations of
mechanical sensory neurons or neuronal populations encoding for
immediate and late activation at the spinal cord level, except for
-opioid receptors (21). Serotonin (5-HT) appears relatively
selective of visceral nociception. This mediator is released at the
intestinal level by enterochromaffin cells, platelets, and mast cell
degranulation and subsequently acts on visceral afferents through
specific receptors (for review, see Ref. 27). 5-HT is involved in the
activation of primary afferents; studies on pseudoaffective
(cardiovascular) reflex responses to gut distension have suggested an
action through a 5-HT3 receptor subtype coupled to a sodium
channel present on primary afferent endings. Indeed, 5-HT3
antagonists injected intravenously at low doses exert potent visceral
analgesic effects in response to gut distension in different rat models
of visceral pain; several studies, however, pointed out the
heterogeneity of the responses to these antagonists in animal models of
distension and the lack of dose-response relationships. Moreover,
5-HT3 receptor antagonists do not appear to be more
efficacious in conditions of hyperalgesia (20). 5-HT3
receptors are also expressed within the central nervous system in
limbic structures, brain stem, and spinal cord. At the dorsal horn
level, they are localized presynaptically in the superficial laminae
but also on intrinsic neurons. These receptors are expressed by
enkephalinergic neurons and play a role in spinal analgesia produced by
5-HT (32). Some other 5-HT receptor subtypes, such as
5-HT1A, are involved at central and peripheral levels in
the mediation of visceral nociceptive inputs. 5-HT1A
receptor agonists, such as
DL-8-hydroxy-2-(di-n-propylamino)tetralin
(8-OH-DPAT), exert centrally-mediated antinociception on gastric
distension (26), whereas 5-HT1A antagonists have an
antinociceptive effect at the rectocolonic level in hyperalgesia models
(4). The involvement of 5-HT4 receptors in the modulation
of visceral afferents is not known; however, 5-HT4 receptor
antagonists are able to potentiate the inhibitory effects of
5-HT3 antagonists on visceral pain (28).
Bradykinin (BK) participates in the mediation of the hyperalgesia
caused by irritant substances in several animal models. Two BK receptor
types have been identified. Although most of the demonstrated
pathophysiological actions of BK are mediated through the
B2 receptor type, there is increasing evidence that
B1 receptors, which preferentially bind the BK metabolite
[des-Arg9]-BK, are selectively
upregulated during processes that follow some types of intestinal
tissue injury. Recently, a link between B1 receptor
activation and inflammation-induced nociception has been identified,
but its site of expression remains unclear, particularly for visceral
pain, even though B1 receptors are chronically expressed in
viscera and B1 receptor activation results in the release
of hyperalgesic substances such as prostanoids (1). Endogenous NGF
released from mast cells under various stimuli may increase the primary
afferent sensitivity to BK (16). At the visceral level, antinociceptive
effects of BK antagonists have already been shown with NPC-567, a
nonselective B1 and B2 receptor antagonist that
decreases pain induced by intraperitoneal administration of acetic acid
and urate crystals. B2 antagonists are also active on acute
inflammation-induced rectal allodynia (for review, see Ref. 3), and
both B1 and B2 antagonists attenuate or
suppress postinfection-induced jejunal hyperalgesia (18).
Tachykinins have an important role in the transmission of nociceptive
messages from the gut. Many C-afferent fibers have "silent receptors" for neurokinins that can be sensitized by inflammatory processes in peripheral tissues. Increased expression of both NK1 and NK2 receptors, as well as SP and
neurokinin A (NKA), have been described at spinal and peripheral levels
in pain-associated gut inflammation. The recording of primary afferent
discharges at the dorsal horn level in response to colonic distension
has largely confirmed that the blockade of NK1 or
NK2 receptors reduces neuronal activation. Recently, a more
intense effect has been found for a selective NK3 receptor
blocker, suggesting that neurokinin B (NKB) and its NK3
receptors located at the periphery play a role in inflammation-induced
gut hyperalgesia (15). Interestingly, immunohistological studies have
identified NK3 receptors on intrinsic primary afferent
neurons (IPANs) but not on extrinsic afferent neurons (17). Moreover,
NKB is coexpressed in neurons that also contain preprotachykinin A,
which synthesize SP and NKA at the myenteric and
submucosal plexus levels. The signaling role of IPANs and their
NK3 receptor pelvic nerve terminals is probably important
in colonic hyperalgesia. In agreement with such hypotheses is the
observation that NK3 antagonists are not active on the firing of pelvic afferents in response to distension of the urinary bladder, which is devoid of IPANs (15). Indeed, IPANs play a primary
transducer role: distension could activate stretch-sensitive ion
channels on IPANs where NK3 receptors, in response to NKB, may facilitate the distension-induced release of a signaling molecule which in turn activates primary afferents. The intraperitoneal injection of acetic acid induces visceral pain and inhibits gastric emptying in rats. Tachykinin NK1 receptor antagonists, such
as RP-67580, are able to selectively suppress the peritoneogastric motor inhibitory reflex, and the NK2 receptor antagonist
SR-48968 selectively reduces abdominal cramps. In contrast, abdominal
surgery-induced gastric ileus does not seem to be modified by
NK1 antagonists. All of these data suggest that nociceptive
messages from the inflamed rat peritoneum involve NKA rather than SP as
mediator and/or, at least, tachykinin NK2 receptors. For
the lower gut, even in a situation of normalgesia, the same selectivity
of effects was observed for NK1 (CP-96345, RP-67580) and
NK2 (SR-48968, MEN-10376) receptor antagonists:
NK1 antagonists reverse rectal distension-induced colonic
inhibition without affecting the abdominal response, and NK2 antagonists selectively reduce visceral pain as
assessed by the number of abdominal contractions. NK3
receptors at the periphery participate in both rectocolonic inhibitory
reflex and nociception triggered by rectal distension. Finally, from
the presently available data on visceral pain in animal models, it can
be concluded that NK1 receptor blockade prevents visceral
hyperalgesia related to inflammation through an anti-inflammatory
action but is inactive against an established hypersensitivity, whereas
both NK2 and NK3 receptor blockade reduce
visceral pain by acting both centrally and peripherally for
NK2 receptors and only at the periphery for NK3 receptors.
Calcitonin gene-related peptide (CGRP) is present in most splanchnic
afferents, and CGRP immunoreactivity almost disappears from the gut
after either splanchnic nerve section or treatment with the sensory
neurotoxin capsaicin. About 50% of CGRP immunoreactive afferent
neurons also contain SP/NKA immunoreactivity. Moreover, CGRP released
at the spinal cord from central endings of primary afferents is
important in the development of visceral hyperalgesia. Alternatively,
peripherally released CGRP may modify sensory inputs, causing changes
in blood flow, smooth muscle contractions, immune reaction, and/or mast
cell degranulation. The intravenous administration of the
CGRP1 receptor antagonist human
(h)-CGRP-(8-37) suppresses the abdominal cramps
observed after the intraperitoneal administration of acetic acid in
awake rats and blocks the inhibition of gastric emptying induced by
peritonitis, increasing its usefulness in the prevention of both
functional inhibitory reflexes and pain. CGRP is also involved in the
mediation of pain produced by lower gut distension. Thus the CGRP
antagonist h-CGRP-(8-37) reverses the sensitizing effects
(allodynia) of acetic acid on abdominal response to colorectal
distension after intracolonic administration of acetic acid (24).
NMDA receptors are believed to play only a small part in the
nociceptive response evoked by acute stimulation of normal somatic tissues but would play a much larger part in the
hyperalgesic response to peripheral injury and inflammation. The role
of NMDA receptors in the transmission of nociceptive messages from the gut induced by colorectal distension has been suspected for a long time
(5), but recent studies suggest that other excitatory amino acids, such
as quisqualic and kainic acids, may be involved in the mediation of
visceral pain through
-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors at
the spinal cord level (29). Moreover, recent studies also suggest that
glutamate and NMDA receptors are involved at the peripheral level in
the sensitization of primary afferent terminals during inflammation of
the gut or urinary tract (22). NMDA receptors and glutamate have also
been detected in intrinsic sensory neurons at the intestinal level. The
predominant subtypes of NMDA receptors located in the gut are not
known, but NMDA receptor antagonists acting more selectively on
NR1/NR2B subunits have recently been shown to
exert marked visceral antinociceptive effects (unpublished
observations). Interestingly, NMDA receptor ion channel blockers, such
as nemantine and ketamine, or the glycine site antagonist MRZ 2/576
inhibit nociceptive reflexes evoked from the normal ureter, suggesting
that, in contrast to somatic pain, NMDA receptors are involved in the
processing of acute nociceptive inputs from noninflamed viscera (22).
Moreover, classical noncompetitive NMDA receptor antagonists strongly
inhibit the nociceptive response due to the increased sensitivity
provoked by visceral inflammation (5). Therefore, we can speculate that
NMDA antagonists at certain doses may act selectively on visceral hyperalgesia.
Ion channels located either on primary afferents or postsynaptically at
the spinal cord level are interesting targets for the development of
visceral antihyperalgesic drugs. Drugs binding to the
2
-subunits
of calcium channels, such as gabapentin and pregabalin, prevent the
hypersensitivity to colorectal distension induced by septic shock, TNBS
colitis, or stress (unpublished observations). They are active at a
lower dose on the hyperalgesia component than on the basal response to
a mechanical stimulus and possibly have a central site of action.
Similarly, compounds that inactivate voltage-dependent sodium channels
may prevent the in vivo glutamate release at the spinal cord, impairing
the transmission of the nociceptive message. Moreover, molecules
derived from trimebutine (JO-1614) that bind on dorsal root ganglion
neuron sodium channels have been shown to reduce the
inflammation-induced rectal hypersensitivity in rats (25).
Many reports pointed out that µ- and
-opioid agonists lessen the
nociceptive response to either peritoneal administration of irritants
or intestinal distension (for review, see Ref. 3). It was also shown
that
-agonists may act peripherally to prevent visceral pain and are
more active in inflammatory conditions.
-Agonists interact on
sensory neurons of the periphery, with receptors coupled to multiple
high voltage-activated (HVA) calcium channels by a
pertussis toxin (PTX)-sensitive G protein pathway; inhibition of calcium channel function likely contributes, at least in
part, to the peripheral analgesic action of
-agonists in visceral
nociception (30). Somatostatin (SST) and its SST1 and
SST2 receptors have been identified within the spinal cord, with a localization implying that they can play a modulatory role in
pain processing comparable to that of GABAA and
2-adrenergic receptors (Fig. 2).
 |
FROM PRECLINICAL TO CLINICAL STUDIES |
Although many substances have been tested on models of gut
distension-induced nociception, only a few of them were evaluated in
multiple models of hyperalgesia to distension in rats (Table 1). Indeed, the evaluation in multiple
models is a prerequisite for selection of active compounds for clinical
trials in FBD. Tachykinin NK2 receptor antagonists have
been found active in many of these models, including
Nippostrongylus brasiliensis postinfection-, stress-, and
TNBS-induced colitis, but have not been tested on lipopolysaccharide-induced rectal allodynia. Despite recent data suggesting that they modulate the activity of primary afferents, their
site of action remains unknown in these models. In addition, their
evaluation in humans has not been published so far.
-Agonists, like
fedotozine, are active in several preclinical models of gut hyperalgesia; fedotozine has also been shown to increase pain threshold
in IBS patients when infused intravenously (7). 5-HT3 antagonists, such as cilansetron and alosetron, are active in several
models of distension, with a limited improvement of efficacy in models
of hyperalgesia, including intracolonic glycerol-induced abdominal
cramps (2), an effect unrelated to their influence on colonic tone. In
all of these models, the efficacy of 5-HT3 antagonists is
not dose related. A 3-wk treatment of IBS patients with alosetron does
not affect the threshold of pressure inducing the first sensation of
pain; however, this threshold occurs at a larger volume of inflation of
the bag, evidencing a relaxatory effect on the distal colon that could
partly account for the improvement of symptoms (8). 5-HT4
receptor agonists, like tegaserod, have been recently described as
active on symptoms in IBS constipated patients with an improvement of
pain scores. However, until now a possible role of 5-HT4 in
the modulation of gut sensitivity has never been investigated.
5-HT1A receptor antagonists, such as WAY-100425, are active
in various models of lower gut hypersensitivity (4), whereas
5-HT1A agonists, including 8-OH-DPAT, increase the
threshold of pain response to gastric distension. In humans, both
5-HT1A agonists and 5-HT1D antagonists affect
the threshold of gastric distension-induced pain, but only
5-HT1D antagonists, like sumatriptan, are found to be
active on the symptoms of non-ulcer dyspepsia (31). B1 and
B2 receptor antagonists have also been found to be active
in models of inflammation- and hypermastocytosis-induced rectal
allodynia; however, they have not been tested by the oral route and
never for visceral pain in humans. B1 receptor antagonists are of special interest since B1 receptors are expressed in
the gut only under inflammatory conditions. Gabapentin and
pregabalin, two selective agonists of the
2
-subunits of calcium
channels, are able to modulate glutamate release at the dorsal horn
level in rodents and have been found to be active in visceral pain
induced by septic shock, inflammation, colonic glycerol, and stress, at doses similar to those active in many models of somatic and neuropathic pain. Until now, they have not been tested on visceral pain in humans.
Several groups of investigators have demonstrated that octreotide, a
cyclic SST analog, is able to increase the threshold of sensitivity to
colorectal barostatic distension in healthy subjects and to restore a
normal level of sensitivity in IBS patients (for review, see Ref. 3).
In the upper gut of healthy subjects, SST also reduces the symptoms of
perception of fullness in response to gastric distension.
Subcutaneously administered octreotide has been shown to relieve
chronic refractory epigastric pain symptoms severe enough to provoke
nutritional impairment over long periods of time (1-2 yr) with
only minor side effects (12).
 |
CONCLUSIONS |
Even though the presence of gut hypersensitivity to distension has not
been demonstrated in all patients with FBD, abdominal pain remains a
major cause of patients consulting a gastroenterologist. Furthermore,
barostat studies have shown that the majority of patients experiencing
pain have an increased sensitivity of at least one part of the gut. In
these patients, pharmacological agents that selectively target visceral
hypersensitivity may be used successfully. The recent discovery of key
neuropeptides and other mediators that can be involved at peripheral
and central levels, and the characterization of their receptors, has
led to the development of many preclinical models with which to
evaluate their possible involvement in gut hyperalgesia. Drugs acting
selectively on these receptors are now available, but their ability to
improve symptoms in clinical situations remains to be determined for
the most promising agents.
 |
FOOTNOTES |
*
Third in a series of invited articles on Pathobiology of
Visceral Pain: Molecular Mechanisms and Therapeutic Implications.
Address for reprint requests and other correspondence: L. Buéno, INRA, Neuro-Gastroenterology and Nutrition Unit, 180, Chemin de Tournefeuille, BP3, 31931 Toulouse Cedex 9, France (E-mail:
lbueno{at}toulouse.inra.fr).
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