TRPV1 and the gut: from a tasty receptor for a painful vanilloid to
a key player in hyperalgesia
Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universita ¨tsplatz 4, A-8010 Graz, Austria
Accepted 1 July 2004
Available online 24 August 2004
Capsaicin, the pungent ingredient in red pepper, has been used since ancient times as a spice, despite the burning sensation associated with
its intake. More than 50 years ago, Nikolaus Jancso ´ discovered that capsaicin can selectively stimulate nociceptive primary afferent neurons.
The ensuing research established that the neuropharmacological properties of capsaicin are due to its activation of the transient receptor
potential ion channel of the vanilloid type 1 (TRPV1). Expressed by primary afferent neurons innervating the gut and other organs, TRPV1 is
gated not only by vanilloids such as capsaicin, but also by noxious heat, acidosis and intracellular lipid mediators such as anandamide and
lipoxygenase products. Importantly, TRPV1 can be sensitized by acidosis and activation of various pro-algesic pathways. Upregulation of
TRPV1 in inflammatory bowel disease and the beneficial effect of TRPV1 downregulation in functional dyspepsia and irritable bladder make
this polymodal nociceptor an attractive target of novel therapies for chronic abdominal pain.
D 2004 Elsevier B.V. All rights reserved.
Keywords: TRPV1; Vanilloid; Hyperalgesia
From Drosophila to man: capsaicin is not just a matter of taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
TRPV1 as a polymodal detector of painful physical and chemical stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.Milestones in the identification of the bcapsaicin receptorQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. TRPV1 as a member of a sensory ion channel superfamily. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.TRPV1 as a sensor relevant to nociception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.TRPV1 as a polymodal nociceptor that can be sensitized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contribution of TRPV1 to gastrointestinal function in health and disease . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Capsaicin as a neuropharmacological tool: demonstration that sensory neurons are important for gut function. . . . . .
3.2.Capsaicin-sensitive afferent neurons in the gut: an incomplete match with neurons expressing TRPV1 . . . . . . . . .
3.3.Implications of TRPV1 in gastrointestinal mucosal functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.Participation of TRPV1 in gastrointestinal nociception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Alterations of TRPV1 expression in gastrointestinal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Therapeutic options provided by TRPV1 channel blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0014-2999/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
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European Journal of Pharmacology 500 (2004) 231–241
1. From Drosophila to man: capsaicin is not just a matter
Few would object that seasoning heightens the joy of a
meal, and history tells us that wars have been fought to
ensure an unbroken supply of spices. One of the most
unusual seasonings is the vanilloid derivative capsaicin, the
pungent ingredient in red peppers of the genus Capsicum
including chilli and jalapen ˜o, given that the sensory
experience associated with its intake ranges from pleasant
to painful. This is probably a reason why mankind is divided
into people who love and those who abhor red pepper, with
a distinct geographical distribution. However, the great
divide between pleasant and repellent sensations associated
with capsaicin is rooted much deeper within the vertebrate
kingdom. Individuals that have ever been exposed to
capsaicin powder spread in the air know that, for a few
milliseconds, the attractive smell/taste of vanilla precedes
the repellent experience of severe irritation in the eyes, nose,
mouth and airways that immediately follows. Birds, to the
contrary, are not repelled by capsaicin at all, because the
avian ortholog of the transient receptor potential (TRP) ion
channel of the vanilloid type 1 (TRPV1), which represents
the bcapsaicin receptorQ in mammals, lacks the vanilloid
binding site (Jordt and Julius, 2002). It may be that
capsaicin offers only a favourable vanilla flavour to birds,
providing an incentive for these creatures to distribute the
seeds of red pepper.
In the past years, TRP ion channels have become a hot
spot in sensory physiology, pharmacology and pain
research. An explosion of research has revealed that TRP
ion channels represent an ancient sensory apparatus of the
cell, responding to temperature, touch, sound, osmolarity,
pheromones, taste, pain and other stimuli (Clapham, 2003).
TRP ion channels were first described in Drosophila, but
now are known to occur throughout the animal kingdom.
Humans use TRP channels to appreciate sweet, bitter and
umami tastes (Zhang et al., 2003) and to discriminate
warmth, heat and cold (Clapham, 2003; Patapoutian et al.,
2003). TRPV1 has attracted particular attention, because it
is activated not only by capsaicin, but also by noxious heat,
acidosis and other painful stimuli.
2. TRPV1 as a polymodal detector of painful physical
and chemical stimuli
2.1. Milestones in the identification of the bcapsaicin
The prime trace to the discovery of TRPV1 was laid
more than 50 years ago by the Hungarian pharmacologist
Nikolaus Jancso ´ who realized that the sensation of
burning pain elicited by capsaicin is due to stimulation
of nociceptive afferent neurons (Jancso ´, 1960). Studies
into the structure–activity relationship of capsaicin con-
geners led Szolcsa ´nyi and Jancso ´-Ga ´bor (1975) to
propose that capsaicin excites afferent neurons via specific
receptors for this vanilloid. This concept was corroborated
by the development of a capsaicin antagonist, capsazepine
(Bevan et al., 1992), and the identification of specific
binding sites for resiniferatoxin (Szallasi and Blumberg,
1999), a compound sharing structural and pharmacolog-
ical similarities with capsaicin. The final proof came in
1997 when the bcapsaicin receptorQ was cloned and, at
that time, termed vanilloid receptor of type 1 (VR1;
Caterina et al., 1997). Following the discovery of several
related ion channels, all of which belong to the TRP
Fig. 1. Membrane topology of the rat TRPV1 showing amino acid positions critical for channel activation by vanilloids (capsaicin and resiniferatoxin) and lipid
ligands, on the one hand, and H+ions, on the other hand. E-600 is important for TRPV1 sensitization by H+ions, whereas E-648 plays an important role in
acidosis-induced gating of TRPV1.
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
channel superfamily, VR1 was renamed TRPV1 (Clapham
et al., 2003).
2.2. TRPV1 as a member of a sensory ion channel
The mammalian TRP channels comprise six related
protein families (TRPA, TRPC, TRPM, TRPML, TRPP,
and TRPV), among which TRPV1 is the prototypical
member of the TRPV subfamily which currently comprises
six members, TRPV1–TRPV6 (Clapham et al., 2003). All
members of the TRP superfamily are putative six trans-
membrane (TM) polypeptide subunits that assemble as
tetramers to form cation-permeable pores (Clapham, 2003).
Like many other TRP channels, TRPV1 is a nonselective
cation channel with high permeability for Ca2+(Caterina et
al., 1997; Clapham, 2003). Cations are selected for
permeation by the extracellular pore loop between TM5
and TM6 (Fig. 1), and in the tetrameric TRP structure the
four TM5-pore loop-TM6 elements face the centre of the
channel to form the gate and its selectivity filter (Clapham,
2003). TRPV1 is most likely a homotetramer (Kedei et al.,
2001), although the existence of heteromultimers of TRPV1
with other members of the TRPV subfamily is possible
(Gunthorpe et al., 2002; Smith et al., 2002).
Built into the cell membrane, TRP channels respond
to a large variety of physical and chemical stimuli, acting
from both within and outside the cell. One of the many
remarkable properties is that TRPV1, TRPV2, TRPV3,
TRPV4, TRPM8 and TRPA1 (ANKTM1) are thermo-
sensors with different working ranges (Table 1), that
enable sensory neurons to monitor a wide spectrum of
temperatures from noxious cold to noxious heat (Pata-
poutian et al., 2003). With these properties, the so-called
thermoTRP channels (Table 1; Patapoutian et al., 2003) are
in a prime position to orchestrate thermosensation and
Another striking property of TRP channels is that they
function as receptor-gated ion channels (Fig. 1, Tables 1 and
2). This is true for the mammalian TRPV1 which, unlike the
avian ortholog, responds to capsaicin and related vanilloids
such as resiniferatoxin, because it contains a vanilloid
binding site which involves several amino acids in TM2 (R-
49), TM3 (Y-511, S-512) and TM4 (M-547, W-549, T-550
in rat; Jordt and Julius, 2002; Chou et al., 2004; Gavva et
al., 2004). Amino acid substitutions at positions 547 and
550 determine the differential vanilloid sensitivity of the
human, rat, rabbit and avian TRPV1 (Jordt and Julius, 2002;
Chou et al., 2004; Gavva et al., 2004). Much as TRPV1 is
the receptor for capsaicin, the hot ingredient in red peppers
of the genus Capsicum (Caterina et al., 1997), TRPA1 is the
receptor for isothiocyanate (mustard oil), the spicy and
irritating ingredient in plants of the genus Brassica such as
mustard, horseradish and wasabi (Jordt et al., 2004). In
contrast, the pleasant cooling sensation caused by menthol
is mediated by TRPM8 which is a thermoTRP channel
operating in a cool temperature range (McKemy et al., 2002;
Peier et al., 2002).
2.3. TRPV1 as a sensor relevant to nociception
The observation that capsaicin elicits burning pain and
neurogenic inflammation (Jancso ´, 1960) was an early hint
that the cellular mechanisms triggered by this vanilloid may
be fundamentally relevant to nociception. This conjecture is
fully borne out by the unique biological properties of
TRPV1 (Fig. 1, Table 2; Caterina and Julius, 2001; Di
Marzo et al., 2002; Gunthorpe et al., 2002; Hwang and Oh,
2002). Thus, human, rat, guinea pig and rabbit TRPV1 is
Key properties of thermoTRP channels
For a detailed review and specific references, see Patapoutian et al. (2003).
Activators and sensitizers of TRPV1
Net effect on
Channel gatingIntracellularly on
TM3/TM4 of TRPV1
TM3/TM4 of TRPV1
E-648 of TRPV1
Acidosis (pH 7–6)
E-600 of TRPV1
Ethanol (0.3–3 %)
bradykinin acting via B2
receptors, and nerve
acting via P2Y2
acting via B2receptors,
displacement of PIP2
S-502 and S-800
of S-116 on TRPV1
For details and references, see text.
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
not only activated by capsaicin, resiniferatoxin and noxious
heat, but also by acidosis (Caterina et al., 1997; Tominaga et
al., 1998; Cortright et al., 2001; Smart et al., 2001; Savidge
et al., 2002; Gavva et al., 2004), ethanol (Trevisani et al.,
2002) and lipid mediators such as anandamide (Zygmunt et
al., 1999; Craib et al., 2001), N-arachidonoyl-dopamine
(NADA; Huang et al., 2002; Premkumar et al., 2004), N-
oleoyl-dopamine (Chu et al., 2003) as well as 12-, 15-, and
5-lipoxygenase products including 12-(S)-hydroperoxy
eicosatetraenoic acid (12-HPETE), 15-HPETE and leuko-
triene B4(Hwang et al., 2000).
The vanilloid and fatty acid agonists bind to an
intracellular site of TRPV1 (Hwang et al., 2000; Jordt et
al., 2000; Welch et al., 2000; Premkumar and Ahern, 2000;
McLatchie and Bevan, 2001; De Petrocellis et al., 2001;
Jung et al., 2002; Chou et al., 2004; Gavva et al., 2004), and
anandamide targets the same recognition site as capsaicin
(Jordt and Julius, 2002). The intracellular location of the
lipid ligand-binding site suggests that endogenous TRPV1
agonists may come from within the cell (Hwang and Oh,
2002) following noxious stimulation, and the relatively low
potency with which extracellularly administered ananda-
mide or NADA activates TRPV1 may be due to their limited
access to the intracellular recognition domain (Premkumar
et al., 2004). In addition, the pharmacology of anandamide
is complicated by its agonism at cannabinoid CB1receptors
H+ions have long been suspected to be the endogenous
activators of the bcapsaicin receptorQ (Bevan and Geppetti,
1994). Both the capsaicin-sensitive TRPV1 (Caterina et al.,
1997; Tominaga et al., 1998) and the capsaicin-insensitive
TRPV4 (Suzuki et al., 2003) are gated by a drop in the
extracellular pH below 6 (Caterina et al., 1997; Tominaga et
al., 1998; Jordt et al., 2000; Welch et al., 2000; McLatchie
and Bevan, 2001). However, genetic deletion of TRPV1
fails to modify the excitatory effect of acidosis on nodose
ganglion neurons (Kollarik and Undem, 2004), which is in
keeping with the concept that the acid sensitivity of afferent
neurons involves many H+-sensitive ion channels (Holzer,
2.4. TRPV1 as a polymodal nociceptor that can be
An exceptional property of TRPV1 is its sensitization by
H+ions and various pro-algesic pathways (Table 2). Thus,
mild acidosis (pH 7–6) which does not gate TRPV1
sensitizes this channel to other stimuli such as capsaicin
and heat (Tominaga et al., 1998; Cortright et al., 2001;
McLatchie and Bevan, 2001). Unlike the lipid ligands, H+
ions target an extracellular domain of TRPV1 (Jordt et al.,
2000). While the ability of H+ions to sensitize TRPV1 to
heat and other stimuli depends critically on E-600, the ability
ofacidosistogateTRPV1ismediated byE-648 (Fig.1;Jordt
et al., 2000). Acid-induced sensitization of TRPV1 lowers
the temperature threshold for TRPV1 activation so that the
channel becomes active at normal body temperature (Tomi-
naga et al., 1998). This finding has led to the hypothesis that
TRPV1 is a central factor in hyperalgesia (Reeh and Pethf,
2000) and prompted a series of studies into the regulation of
TRPV1 activity by other pro-algesic pathways.
TRPV1 has a number of consensus phosphorylation sites
that can be targeted by protein kinase (PK) A (PKA), PKC
and other kinases. Thus, activation of prostaglandin E2
receptors enhances TRPV1 currents via the cyclic adenosine
monophosphate–PKA pathway (Lopshire and Nicol, 1998),
PKA phosphorylating the cation channel at S-116 and thus
preventing its rapid desensitization (Bhave et al., 2002).
Phorbol esters, oleoylethanolamide, NADA and stimulation
of bradykinin B2receptors or metabotropic P2Y2purino-
ceptors lead to PKC-mediated phosphorylation of TRPV1 at
S-502 and S-800, which enhances the probability of channel
gating by protons, capsaicin, anandamide and/or heat
(Premkumar and Ahern, 2000; Vellani et al., 2001; Crandall
et al., 2002; Kagaya et al., 2002; Numazaki et al., 2002;
Olah et al., 2002; Ahern, 2003; Bhave et al., 2003;
Moriyama et al., 2003; Premkumar et al., 2004). Adenosine
triphosphate can also directly interact with nucleotide-
binding domains of TRPV1 to augment the channel
response to capsaicin (Kwak et al., 2000).
Another mechanism whereby bradykinin, nerve growth
factor and anandamide sensitize TRPV1 involves phospho-
lipase C-mediated hydrolysis of phosphatidylinositol-4,5-
bisphosphate (PIP2) which normally inhibits TRPV1 gating
by agonists (Prescott and Julius, 2003). PIP2binds to a site
within the C-terminal domain of TRPV1, and intracellular
lipid agonists can activate TRPV1 by cleaving PIP2. Indeed,
TRPV1 activation by lipoxygenase products generated
through stimulation of phospholipase A2seems to contrib-
ute to the excitatory action of bradykinin on spinal and vagal
afferents (Shin et al., 2002; Carr et al., 2003). A similar
situation applies to the TRPV1-mediated excitation of vagal
afferents by anandamide, which is likewise inhibited by a
lipoxygenase inhibitor (Kagaya et al., 2002).
A further aspect relevant to TRPV1 activity is its
property to desensitize in the presence of capsaicin, which
depends on extracellular Ca2+and involves binding of
calmodulin to a domain in the C-terminus of TRPV1
(Numazaki et al., 2003; Rosenbaum et al., 2004). It appears
as if a dynamic balance between phosphorylation and
dephosphorylation of TRPV1 by Ca2+-calmodulin-depend-
ent kinase II and calcineurin, respectively, controls the
activation/desensitization state of the channel (Jung et al.,
2004). Furthermore, Y-671 which is critical for the high
Ca2+permeability of TRPV1 participates in the rearrange-
ment of the channel protein leading to desensitization
(Mohapatra et al., 2003). Phosphorylation of TRPV1 at S-
116 and possibly T-370 by PKA likewise prevents its rapid
desensitization and thus increases channel activity (Bhave et
al., 2002; Mohapatra and Nau, 2003).
From these findings, it is emerging that TRPV1
integrates many noxious stimuli and thus plays a significant
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
role in setting the gain of nociceptors. As acidosis,
prostaglandins, bradykinin, adenosine triphosphate and
nerve growth factor are formed under conditions of injury
and inflammation, they could bring about hyperalgesisa by
lowering the temperature threshold of TRPV1 to a level
permissive for channel gating at normal body temperature
(Reeh and Petho ¨, 2000). The relevance of TRPV1 to
inflammatory hyperalgesia is borne out by the finding that
TRPV1 knockout mice do not develop thermal hyperalgesia
in response to experimental inflammation or adenosine
triphosphate stimulation (Caterina et al., 2000; Davis et al.,
2000; Moriyama et al., 2003).
3. Contribution of TRPV1 to gastrointestinal function in
health and disease
3.1. Capsaicin as a neuropharmacological tool:
demonstration that sensory neurons are important for gut
Capsaicin has been used since ancient times both as a
spice and a traditional treatment for gastrointestinal disease.
The biological effects of capsaicin were little understood
until it was discovered that capsaicin exerts two distinct
actions on sensory neurons, an immediate but transient
excitation followed by a long-lasting desensitization to
capsaicin and other sensory nerve stimuli (Jancso ´, 1960).
Both actions were subsequently employed to probe sensory
neuron functions in many organs including the gut (Holzer
and Bartho ´, 1996; Holzer, 1998). These studies had an
important impact on gastrointestinal physiology and path-
ophysiology as they brought to light that afferent neurons
participate in the control of gastrointestinal blood flow,
mucosal ion transport, mucosal inflammation, mucosal
protection, mucosal repair, motor activity and nociception
(Holzer and Bartho ´, 1996; Holzer, 1998). There is now
increasing awareness that hypersensitivity of sensory
neurons and a disturbed gut–brain axis contribute to
functional bowel disorders such as dyspepsia and irritable
bowel syndrome (Holzer, 2002).
3.2. Capsaicin-sensitive afferent neurons in the gut: an
incomplete match with neurons expressing TRPV1
It was long before TRPV1 was identified that a subgroup
of primary sensory neurons had been classified as
bcapsaicin-sensitive afferent neuronsQ on the basis of their
susceptibility to the excitatory and desensitizing action of
capsaicin (Szolcsa ´nyi, 1982). Typically, capsaicin-sensitive
afferents have small to medium-sized cell bodies with
mostly unmyelinated fibres and contain peptide transmitters
among which calcitonin gene-related peptide and substance
P are the most prominent (Holzer, 1991). After the
identification of TRPV1, it has become possible to study
the distribution of the bcapsaicin receptorQ by immunocy-
tochemistry and in situ hybridization. As expected, TRPV1
has been localized to sensory neurons originating from the
trigeminal, nodose and dorsal root ganglia in which TRPV1
is preferentially expressed by small somata that give rise to
unmyelinated fibres (Caterina et al., 1997; Helliwell et al.,
1998; Guo et al., 1999; Michael and Priestley, 1999;
Ichikawa and Sugimoto, 2003; Patterson et al., 2003; Ward
et al., 2003; Robinson et al., 2004; Schicho et al., 2004;
Zhang et al., 2004). However, it turned out that the group of
capsaicin-sensitive afferent neurons, as defined in neuro-
chemical, neurophysiological and neuropharmacological
terms, does not completely match with the population of
neurons that express TRPV1-like immunoreactivity
(TRPV1-LI) or TRPV1 messenger ribonucleic acid
(mRNA). A remarkable aspect of this mismatch is that
TRPV1 is much wider distributed than envisaged from the
One instance of mismatch relates to the brain. While
sensitivity to capsaicin is thought to be a rather exclusive
property of primary afferent neurons (Holzer, 1991; Szallasi
and Blumberg, 1999), TRPV1 mRNA and TRPV1-like
binding sites are widely distributed in the brain (Mezey et
al., 2000), albeit at a lower level than in the spinal ganglia
(Sanchez et al., 2001). The presence of TRPV1 in the brain
fits with previous findings that neurons in discrete fore- and
hindbrain areas including the preoptic area of the hypothal-
amus are susceptible to the neurotoxic action of capsaicin
(Szolcsa ´nyi, 1982; Ritter and Dinh, 1988).
Another example of mismatch concerns the chemical
coding of TRPV1-expressing sensory neurons. Capsaicin-
sensitive afferents abound with calcitonin gene-related
peptide and substance P (Green and Dockray, 1988; Holzer,
1991), whereas these neuropeptides are, in general, rare in
TRPV1-positive dorsal root ganglion neurons (Guo et al.,
1999). There is, however, a substantial coexpression of
calcitonin gene-related peptide and TRPV1 in visceral
sensory neurons (Green and Dockray, 1988; Perry and
Lawson, 1998; Ward et al., 2003; Robinson et al., 2004).
A third instance of mismatch is found in the gut.
Functional studies have indicated that the population of
gastrointestinal capsaicin-sensitive neurons is constituted
by extrinsic primary afferents, whereas intrinsic enteric and
extrinsic autonomic neurons do not directly respond to
capsaicin (Holzer, 1991, 1998; Holzer and Bartho ´, 1996).
Indeed, Patterson et al. (2003), Ward et al. (2003) and
Schicho et al. (2004) have failed to detect TRPV1-LI in
enteric neurons of the rat, guinea pig and mouse gastro-
intestinal tract, which implies that the numerous TRPV1-
positive nerve fibres that occur in the enteric nerve
plexuses, musculature and mucosa represent processes of
spinal afferents and, in the stomach, of some vagal
afferents. This conjecture is strongly supported by the
disappearance of TRPV1 mRNA from the rat stomach
following extrinsic denervation (Schicho et al., 2004).
Other investigators, though, report that TRPV1-LI is
expressed by enteric neurons of the guinea pig, porcine
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
and human intestine (Poonyachoti et al., 2002; Anavi-
Goffer and Coutts, 2003; Chan et al., 2003). In addition,
TRPV1 mRNA, TRPV1 protein and TRPV1-like binding
sites have been found on rat gastric epithelial cells
(Nozawa et al., 2001; Kato et al., 2003), which is
reminiscent of the presence of TRPV1 on epithelial cells
of the urinary bladder where this ion channel acts as a
sensor relevant to bladder function (Birder et al., 2001).
Capsaicin has been reported to excite enteric neurons
(Takaki and Nakayama, 1989), and it appears worth re-
investigating this effect which previously was thought to
be due to transmitter release from extrinsic afferents.
3.3. Implications of TRPV1 in gastrointestinal mucosal
Extensive studies involving capsaicin have demonstrated
that capsaicin-sensitive afferent neurons participate in the
regulation of gastrointestinal circulation, secretion, mucosal
homeostasis, motility and nociception (Holzer and Bartho ´,
1996; Holzer, 1998). These tasks are brought about by two
different modes of operation: an afferent and an efferent-like
function (Maggi, 1995; Holzer and Maggi, 1998). By
conveying information from the gut to the spinal cord and
brainstem, capsaicin-sensitive afferents contribute to gastro-
intestinal sensation and constitute the afferent arm of
autonomic and neuroendocrine reflex circuits relevant to
digestion. Other afferents subserve a local efferent-like
function, which is mediated by release of calcitonin gene-
related peptide, substance P and other mediators from their
peripheral fibres, these transmitters in turn acting on
gastrointestinal effector systems (Maggi, 1995; Holzer,
The efferent-like mode of operation is exemplified by the
reactions of the rat gastric mucosa to luminal capsaicin
exposure or acid backdiffusion (Holzer, 1998). Both stimuli
increase mucosal blood flow through a peripheral circuitry
and initiate other mechanisms of defence such as bicar-
bonate and mucus secretion (Holzer, 1998, 2002). In
addition, capsaicin-sensitive neurons participate in the
feedback regulation of gastric acid secretion: as they are
activated by secreted acid, they release calcitonin gene-
related peptide which, via somatostatin release, halts further
acid secretion (Manela et al., 1995; Holzer, 1998). While the
gastric hyperaemic response to luminal acid backdiffusion is
mediated by spinal afferents, the afferent signalling of
gastric acid challenge to the brain is carried by vagal
afferents (Schuligoi et al., 1998; Lamb et al., 2003). Thus,
the local efferent-like and afferent functions are subserved
by different populations of sensory neurons (Holzer and
The capsaicin-evoked gastric hyperaemia, gastric
mucosal protection and duodenal bicarbonate secretion in
the rat are mediated by TRPV1 because they are antago-
nized by the TRPV1 blocker capsazepine (Tashima et al.,
2002; Kagawa et al., 2003; Kato et al., 2003; Horie et al.,
2004). The gastric mucus secretion evoked by stimulation of
protease-activated receptor-2 (PAR-2) is likewise blunted by
capsazepine (Kawabata et al., 2002), which suggests a link
between PAR-2 and TRPV1 (Table 3). In contrast, the acid-
induced mucosal hyperaemia in the stomach remains
unaltered by capsazepine (Tashima et al., 2002), while the
acid-induced vasodilatation in the duodenum is blunted by
this TRPV1 blocker (Table 3; Akiba et al., 1999). Since,
however, the acid-evoked secretion of duodenal bicarbonate
is left unchanged by capsazepine (Kagawa et al., 2003), it
appears as if there are regional differences in the receptor
mechanisms whereby acid challenge activates afferent
neurons in the foregut.
While TRPV1 in the foregut mediates reactions that
support mucosal homeostasis, TRPV1 in the pancreas,
ileum and colon facilitates processes of inflammation and
tissue damage (Table 3). For instance, experimental
pancreatitis induced by caerulein (Nathan et al., 2001),
ileitis induced by Clostridium difficile toxin A (McVey and
Vigna, 2001) and colitis induced by dextrane sulphate
(Kihara et al., 2003) are significantly ameliorated by
capsazepine. Albeit it awaits to be disclosed how these
inflammatory stimuli are linked to TRPV1, there is
upcoming evidence that C. difficile toxin A enhances the
formation of anandamide and 2-arachidonoyl glycerol in the
mucosa and that these mediators, in turn, activate TRPV1
(McVey et al., 2003). TRPV1-mediated excitation of
sensory nerve terminals releases substance P which activates
enteric neurons, mast cell and other immune cells and thus
leads to hypersecretion, inflammation and mucosal damage
(McVey and Vigna, 2001).
3.4. Participation of TRPV1 in gastrointestinal nociception
The molecular characteristics of TRPV1 as a polymodal
nociceptor and its association with nociceptive afferent
Implications of TRPV1 in gastrointestinal functions
Gastrointestinal functionType of evidenceReferences
Mucus secretion in the rat
stomach evoked by
stimulation of protease-
Vasodilatation in the rat
duodenum caused by
exposure to luminal acid
Inflammation of mouse
pancreas induced by
Inflammation of rat ileum
caused by Clostridium
difficile toxin A
Inflammation of rat ileum
caused by anandamide
Inflammation of rat colon
caused by dextrane
Kawabata et al.,
Akiba et al., 1999
Nathan et al., 2001
McVey and Vigna,
McVey et al., 2003
Kihara et al., 2003
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
nerve fibres attribute this ion channel a particular role in
pain and hyperalgesia. The gut is innervated by two
populations of extrinsic afferents, vagal and spinal, both
of which express TRPV1 (Caterina et al., 1997; Helliwell et
al., 1998; Guo et al., 1999; Michael and Priestley, 1999;
Ichikawa and Sugimoto, 2003; Patterson et al., 2003;
Robinson et al., 2004; Ward et al., 2003; Schicho et al.,
2004; Zhang et al., 2004). Of the nodose ganglion neurons
that innervate the rat stomach, 42–80% stain for TRPV1,
whereas 71–82% of the dorsal root ganglion neurons
projecting to the rat stomach and mouse colon, respectively,
express TRPV1 (Patterson et al., 2003; Robinson et al.,
2004; Schicho et al., 2004). Most TRPV1-positive nerve
fibres in the gut appear to be processes of spinal afferents,
since the level of TRPV1-LI in gastrointestinal terminals of
nodose ganglion neurons is very low (Patterson et al., 2003;
Ward et al., 2003; Schicho et al., 2004). This may explain
why the proportion of capsaicin-sensitive fibres among
vagal afferents supplying the oesophagus and stomach is
V30% (Berthoud et al., 1997; Blackshaw et al., 2000).
Capsaicin stimulates, most likely via TRPV1, extrinsic
afferents of the gut (Maubach and Grundy, 1999; Su et al.,
1999; Blackshaw et al., 2000), and administration of
capsaicin into the lumen of the alimentary canal evokes
pain in humans (Hammer et al., 1998; Drewes et al., 2003;
Schmidt et al., 2004) and mice (Laird et al., 2001; Kawao et
al., 2004). For instance, application of capsaicin to the
human jejunum induces pain whose abdominal localization
and perceptional quality are similar to distension-induced
pain. Since it does not stimulate jejunal motility and does
not alter jejunal mechanosensitivity, capsaicin is thought to
evoke pain by stimulation of jejunal chemoreceptors,
presumably TRPV1 (Schmidt et al., 2004).
Direct evidence for a role of TRPV1 in the pain associated
with gastrointestinal disease has not yet been provided, but
there are accumulating hints at such an implication. The
observation that TRPV1 is relevant to sensitization of dermal
afferents (Caterina et al., 2000; Davis et al., 2000) is matched
by indirect evidence that TRPV1 contributes to gastro-
intestinal hyperalgesia. Thus, administration of capsaicin
into the ileum of patients with an ileal stoma has been
reported to cause mechanical hypersensitivity (Drewes et al.,
2003). Vice versa, application of a PAR-2 agonist into the rat
pancreatic duct sensitizes spinal afferents to capsaicin
(Hoogerwerf et al., 2001), and nociception caused by
intracolonic capsaicin is facilitated after intraperitoneal
administration of a PAR-2 agonist to mice (Kawao et al.,
2004). The molecular mechanism behind the interaction
between PAR-2 and TRPV1 (Hoogerwerf et al., 2001;
Kawabata et al., 2002; Kawao et al., 2004) involves PKC
which phosphorylates TRPV1 and thereby sensitizes it to
activation by other stimuli (Amadesi et al., 2004; Dai et al.,
2004). Since trypsin and tryptase are released during tissue
inflammation, it would appear that PAR-2-mediated sensi-
tization of TRPV1 could be an important mechanism
underlying inflammatory hyperalgesia.
Further indirect evidence for a role of TRPV1 in
abdominal hyperalgesia comes from reports that capsaicin
desensitization is beneficial in patients with functional
dyspepsia or irritable bladder. This approach is based on
the ability of capsaicin to induce a state of sensory
refractoriness (Holzer, 1991) which, depending on the dose
of capsaicin, may be due to desensitization/inactivation of
TRPV1, downregulation of TRPV1 (Szallasi and Blumberg,
1999), loss of sensory neuron excitability or overt neuro-
toxicity (Holzer, 1991; Szallasi and Blumberg, 1999).
Capsaicin pretreatment of rats prevents the behavioural pain
reaction to gastric acid challenge (Lamb et al., 2003) and the
inflammation-induced hypersensitivity to colonic distension
(Plourde et al., 1997; Delafoy et al., 2003). Pretreatment of
rats with SDZ 249-665, a vanilloid compound reproducing
capsaicin desensitization, attenuates inflammatory bladder
hyperreflexia, referred hyperalgesia (Jaggar et al., 2001) and
behavioural pain responses to intraperitoneal acetic acid in
rats (Urban et al., 2000).
Chronic administration of capsaicin is likewise beneficial
in patients with abdominal pain. For instance, intravesical
administration of capsaicin or resiniferatoxin ameliorates the
symptoms of irritable bladder (Cruz, 2004). Intractable
idiopathic pruritus ani is relieved by a 4-week treatment
course with topical capsaicin (Lysy et al., 2003), and daily
intragastric administration of red pepper containing 1.75 mg
capsaicin for 5 weeks significantly reduces epigastric pain
and other symptoms of functional dyspepsia (Bortolotti et
al., 2002). It would hence appear conceivable that gastric
acid-related pain syndromes in the oesophagus and upper
gut are due to acid-induced TRPV1 sensitization.
4. Alterations of TRPV1 expression in gastrointestinal
Acute exposure of the rat gastric mucosa to a noxious
HCl concentration leads to a rise of TRPV1-LI, but not
TRPV1 channel blockers
Blocker (source) References
Bevan et al., 1992
Wahl et al., 2001
Appendino et al.,
et al., 2002
Himmel et al., 2002
Lee et al., 2003
N-alkyl glycine trimers
Arginine-rich hexapeptide R4W2
and related vanilloid analogues
Cinnamide SB-366791 (GlaxoSmithKline)
Suh et al., 2003
Sun et al., 2003
Gunthorpe et al.,
McDonnell et al.,
7-Hydroxynaphthalen-1-yl-urea and -amide
compounds (Johnson & Johnson)
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
TRPV1 mRNA, in dorsal root ganglion neurons innervating
the stomach (Schicho et al., 2004). The density of TRPV1-
LI on nerve fibres of the human colon is enhanced in painful
inflammatory bowel disease (Yiangou et al., 2001) and in
the aganglionic bowel of patients with Hirschsprung’s
disease (Facer et al., 2001). Rectal hypersensitivity and
faecal urgency are associated with a rise in the number of
TRPV1-positive nerve fibres in the muscle, submucosa and
mucosa of the rectum and of TRPV1-positive neurons in the
myenteric and submucosal plexus (Chan et al., 2003).
5. Therapeutic options provided by TRPV1 channel
The polymodal nociceptor properties of TRPV1 make
this ion channel an intriguing target for novel therapies of
abdominal pain and inflammation. It would appear, there-
fore, that TRPV1 channel blockers are of value in
suppressing gastrointestinal hyperalgesia related to inflam-
mation and other circumstances where there is activation
(sensitization) or upregulation of TRPV1. This conjecture is
supported by the beneficial effect of chronic capsaicin
desensitization in functional dyspepsia and irritable bladder
(Bortolotti et al., 2002; Cruz, 2004). Attempts to circumvent
the initial pungency, which capsaicin and related TRPV1
agonists bring about, first led to the use and development of
vanilloid-related compounds with reduced pungency but
preserved ability to desensitize (Szallasi and Blumberg,
1999; Urban et al., 2000). The discovery of the first TRPV1
blocker, capsazepine (Bevan et al., 1992), and the elucida-
tion of the function-relevant domains of TRPV1 have
shifted the focus to the design of highly specific channel
blockers (Table 4). The indication of these drugs is very
likely to comprise visceral hyperalgesia, although the utility
of TRPV1 blockers has not yet been ascertained in
established paradigms of gastrointestinal nociception. In
these tests, it will also be important to explore whether
blockade of TRPV1 interferes with the physiological
function of TRPV1-expressing neurons in gastrointestinal
mucosal homeostasis within the foregut (Holzer, 1998).
Thanks are due to Evelin Painsipp for preparing the
figure. The author’s work is supported by the Austrian
Research Funds, the Jubilee Funds of the Austrian National
Bank, the Austrian Federal Ministry of Education, Science
and Culture and the Zukunftsfonds Steiermark.
Ahern, G.P., 2003. Activation of TRPV1 by the satiety factor oleoyletha-
nolamide. J. Biol. Chem. 278, 30429–30434.
Akiba, Y., Guth, P.H., Engel, E., Nastaskin, I., Kaunitz, J.D., 1999. Acid-
sensing pathways of rat duodenum. Am. J. Physiol. 277, G268–G274.
Amadesi, S., Nie, J., Vergnolle, N., Cottrell, G.S., Grady, E.F., Trevisani,
M., Manni, C., Geppetti, P., McRoberts, J.A., Ennes, H., Davis, J.B.,
Mayer, E.A., Bunnett, N.W., 2004. Protease-activated receptor 2
sensitizes the capsaicin receptor transient receptor potential vanilloid
receptor 1 to induce hyperalgesia. J. Neurosci. 24, 4300–4312.
Anavi-Goffer, S., Coutts, A.A., 2003. Cellular distribution of vanilloid VR1
receptor immunoreactivity in the guinea-pig myenteric plexus. Eur. J.
Pharmacol. 458, 61–71.
Appendino, G., Harrison, S., De Petrocellis, L., Daddario, N., Bianchi,
F., Schiano Moriello, A., Trevisani, M., Benvenuti, F., Geppetti, P.,
Di Marzo, V., 2003. Halogenation of a capsaicin analogue leads to
novel vanilloid TRPV1 receptor antagonists. Br. J. Pharmacol. 139,
Berthoud, H.-R., Patterson, L.M., Willing, A.E., Mueller, K., Neuhuber,
W.L., 1997. Capsaicin-resistant vagal afferent fibers in the rat gastro-
intestinal tract: anatomical identification and functional integrity. Brain
Res. 746, 195–206.
Bevan, S., Geppetti, P., 1994. Protons: small stimulants of capsaicin-
sensitive sensory nerves. Trends Neurosci. 17, 509–512.
Bevan, S., Hothi, S., Hughes, G., James, I.F., Rang, H.P., Shah, K.,
Walpole, C.S., Yeats, J.C., 1992. Capsazepine: a competitive anta-
gonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107,
Bhave, G., Zhu, W., Wang, H., Brasier, D.J., Oxford, G.S., Gereau,
R.W., 2002. cAMP-dependent protein kinase regulates desensitization
of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 35,
Bhave, G., Hu, H.J., Glauner, K.S., Zhu, W., Wang, H., Brasier, D.J.,
Oxford, G.S., Gereau, R.W., 2003. Protein kinase C phosphorylation
sensitizes but does not activate the capsaicin receptor transient receptor
potential vanilloid 1 (TRPV1). Proc. Natl. Acad. Sci. U. S. A. 100,
Birder, L.A., Kanai, A.J., de Groat, W.C., Kiss, S., Nealen, M.L., Burke,
N.E., Dineley, K.E., Watkins, S., Reynolds, I.J., Caterina, M.J., 2001.
Vanilloid receptor expression suggests a sensory role for urinary bladder
epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 98, 13396–13401.
Blackshaw, L.A., Page, A.J., Partosoedarso, E.R., 2000. Acute effects of
capsaicinongastrointestinalvagalafferents. Neuroscience 96, 407–416.
Bortolotti, M., Coccia, G., Grossi, G., Miglioli, M., 2002. The treatment of
functional dyspepsia with red pepper. Aliment. Pharmacol. Ther. 16,
Carr, M.J., Kollarik, M., Meeker, S.N., Undem, B.J., 2003. A role for
TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve
terminals. J. Pharmacol. Exp. Ther. 304, 1275–1279.
Caterina, M.J., Julius, D., 2001. The vanilloid receptor: a molecular
gateway to the pain pathway. Ann. Rev. Neurosci. 24, 487–517.
Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine,
J.D., Julius, D., 1997. The capsaicin receptor: a heat-activated ion
channel in the pain pathway. Nature 389, 816–824.
Caterina, M.J., Leffler, A., Malmberg, A.B., Martin, W.J., Trafton, J.,
Petersen-Zeitz, K.R., Koltzenburg, M., Basbaum, A.I., Julius, D., 2000.
Impaired nociception and pain sensation in mice lacking the capsaicin
receptor. Science 288, 306–313.
Chan, C.L., Facer, P., Davis, J.B., Smith, G.D., Egerton, J., Bountra, C.,
Williams, N.S., Anand, P., 2003. Sensory fibres expressing capsaicin
receptor TRPV1 in patients with rectal hypersensitivity and faecal
urgency. Lancet 361, 385–391.
Chou, M.Z., Mtui, T., Gao, Y.D., Kohler, M., Middleton, R.E., 2004.
Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the
extracellular side of the S4 transmembrane domain. Biochemistry 43,
Chu, C.J., Huang, S.M., De Petrocellis, L., Bisogno, T., Ewing, S.A., Miller,
J.D., Zipkin, R.E., Daddario, N., Appendino, G., Di Marzo, V., Walker,
J.M., 2003. N-oleoyldopamine, a novel endogenous capsaicin-like lipid
that produces hyperalgesia. J. Biol. Chem. 278, 13633–13639.
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
Clapham, D.E., 2003. TRP channels as cellular sensors. Nature 426,
Clapham, D.E., Montell, C., Schultz, G., Julius, D., 2003. International
Union of Pharmacology: XLIII. Compendium of voltage-gated ion
channels: transient receptor potential channels. Pharmacol. Rev. 55,
Cortright, D.N., Crandall, M., Sanchez, J.F., Zou, T., Krause, J.E., White,
G., 2001. The tissue distribution and functional characterization of
human VR1. Biochem. Biophys. Res. Commun. 281, 1183–1189.
Craib, S.J., Ellington, H.C., Pertwee, R.G., Ross, R.A., 2001. A
Pharmacol. 134, 30–37.
Crandall, M., Kwash, J., Yu, W., White, G., 2002. Activation of protein
kinase C sensitizes human VR1 to capsaicin and to moderate
decreases in pH at physiological temperatures in Xenopus oocytes.
Pain 98, 109–117.
Cruz, F., 2004. Mechanisms involved in new therapies for overactive
bladder. Urology 63 (Suppl. 1), 65–73.
Dai, Y., Moriyama, T., Higashi, T., Togashi, K., Kobayashi, K., Yamanaka,
H., Tominaga, M., Noguchi, K., 2004. Proteinase-activated receptor 2-
mediated potentiation of transient receptor potential vanilloid subfamily
1 activity reveals a mechanism for proteinase-induced inflammatory
pain. J. Neurosci. 24, 4293–4299.
Davis, J.B., Gray, J., Gunthorpe, M.J., Hatcher, J.P., Davey, P.T., Overend,
P., Harries, M.H., Latcham, J., Clapham, C., Atkinson, K., Hughes, S.A.,
Rance, K., Grau, E., Harper, A.J., Pugh, P.L., Rogers, D.C., Bingham,
S., Randall, A., Sheardown, S.A., 2000. Vanilloid receptor-1 is essential
for inflammatory thermal hyperalgesia. Nature 405, 183–187.
Delafoy, L., Raymond, F., Doherty, A.M., Eschalier, A., Diop, L., 2003.
Role of nerve growth factor in the trinitrobenzene sulfonic acid-induced
colonic hypersensitivity. Pain 105, 489–497.
De Petrocellis, L., Bisogno, T., Maccarrone, M., Davis, J.B., Finazzi-
Agro `, A., Di Marzo, V., 2001. The activity of anandamide at
vanilloid VR1 receptors requires facilitated transport across the cell
membrane and is limited by intracellular metabolism. J. Biol. Chem.
Di Marzo, V., Blumberg, P.M., Szallasi, A., 2002. Endovanilloid signaling
in pain. Curr. Opin. Neurobiol. 12, 372–379.
Drewes, A.M., Schipper, K.P., Dimcevski, G., Petersen, P., Gregersen, H.,
Funch-Jensen, P., Arendt-Nielsen, L., 2003. Gut pain and hyperalgesia
inducedby capsaicin:a humanexperimentalmodel. Pain 104, 333–341.
Facer, P., Knowles, C.H., Tam, P.K., Ford, A.P., Dyer, N., Baecker, P.A.,
Anand, P., 2001. Novel capsaicin (VR1) and purinergic (P2X3)
receptors in Hirschsprung’s intestine. J. Pediatr. Surg. 36, 1679–1684.
Garcia-Martinez, C., Humet, M., Planells-Cases, R., Gomis, A., Caprini,
M., Viana, F., De La Pena, E., Sanchez-Baeza, F., Carbonell, T., De
Felipe, C., Perez-Paya, E., Belmonte, C., Messeguer, A., Ferrer-
Montiel, A., 2002. Attenuation of thermal nociception and hyperalgesia
by VR1 blockers. Proc. Natl. Acad. Sci. U. S. A. 99, 2374–2379.
Gavva, N.R., Klionsky, L., Qu, Y., Shi, L., Tamir, R., Edenson, S., Zhang,
T.J., Viswanadhan, V.N., Toth, A., Pearce, L.V., Vanderah, T.W.,
Porreca, F., Blumberg, P.M., Lile, J., Sun, Y., Wild, K., Louis, J.C.,
Treanor, J.J., 2004. Molecular determinants of vanilloid sensitivity in
TRPV1. J. Biol. Chem. 279, 20283–20295.
Green, T., Dockray, G.J., 1988. Characterization of the peptidergic afferent
innervation of the stomach in the rat, mouse, and guinea-pig. Neuro-
science 25, 181–193.
Gunthorpe, M.J., Benham, C.D., Randall, A., Davis, J.B., 2002. The
diversity in the vanilloid (TRPV) receptor family of ion channels.
Trends Pharmacol. Sci. 23, 183–191.
Gunthorpe, M.J., Rami, H.K., Jerman, J.C., Smart, D., Gill, C.H., Soffin,
E.M., Luis Hannan, S., Lappin, S.C., Egerton, J., Smith, G.D., Worby,
A., Howett, L., Owen, D., Nasir, S., Davies, C.H., Thompson, M.,
Wyman, P.A., Randall, A.D., Davis, J.B., 2004. Identification and
characterisation of SB-366791, a potent and selective vanilloid receptor
(VR1/TRPV1) antagonist. Neuropharmacology 46, 133–149.
the bronchus. Br. J.
Guo, A., Vulchanova, L., Wang, J., Li, X., Elde, R., 1999. Immunocy-
tochemical localization of the vanilloid receptor 1 (VR1): relationship to
neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J.
Neurosci. 11, 946–958.
Hammer, J., Hammer, H.F., Eherer, A.J., Petritsch, W., Holzer, P., Krejs,
G.J., 1998. Intraluminal capsaicin does not affect fluid and electro-
lyte absorption in the human jejunum but does cause pain. Gut 43,
Helliwell, R.J., McLatchie, L.M., Clarke, M., Winter, J., Bevan, S.,
McIntyre, P., 1998. Capsaicin sensitivity is associated with the
expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult
rat sensory ganglia. Neurosci. Lett. 250, 177–180.
Himmel, H.M., Kiss, T., Borvendeg, S.J., Gillen, C., Illes, P., 2002. The
arginine-rich hexapeptide R4W2 is a stereoselective antagonist at the
vanilloid receptor 1: a Ca2+imaging study in adult rat dorsal root
ganglion neurons. J. Pharmacol. Exp. Ther. 301, 981–986.
Holzer, P., 1991. Capsaicin: cellular targets, mechanisms of action, and
selectivity for thin sensory neurons. Pharmacol. Rev. 43, 143–201.
Holzer, P., 1998. Neural emergency system in the stomach. Gastro-
enterology 114, 823–839.
Holzer, P., 2002. Sensory neurone responses to mucosal noxae in the upper
gut: relevance to mucosal integrity and gastrointestinal pain. Neuro-
gastroenterol. Motil. 14, 459–475.
Holzer, P., 2003. Acid-sensitive ion channels in gastrointestinal function.
Curr. Opin. Pharmacol. 3, 618–625.
Holzer, P., Bartho ´, L., 1996. Sensory neurons in the intestine. In: Geppetti,
P., Holzer, P. (Eds.), Neurogenic Inflammation. CRC Press, Boca Raton,
FL, pp. 153–167.
Holzer, P., Maggi, C.A., 1998. Dissociation of dorsal root ganglion neurons
into afferent and efferent-like neurons. Neuroscience 86, 389–398.
Hoogerwerf, W.A., Zou, L., Shenoy, M., Sun, D., Micci, M.A., Lee-
Hellmich, H., Xiao, S.Y., Winston, J.H., Pasricha, P.J., 2001. The
proteinase-activated receptor 2 is involved in nociception. J. Neurosci.
Horie, S., Yamamoto, H., Michael, G.J., Uchida, M., Belai, A., Watanabe,
K., Priestley, J.V., Murayama, T., 2004. Protective role of vanilloid
receptor type 1 in HCl-induced gastric mucosal lesions in rats. Scand. J.
Gastroenterol. 39, 303–312.
Huang, S.M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L.,
Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., Miller, J.D.,
Davies, S.N., Geppetti, P., Walker, J.M., Di Marzo, V., 2002. An
endogenous capsaicin-like substance with high potency at recombinant
and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. U. S. A. 99,
Hwang, S.W., Oh, U., 2002. Hot channels in airways: pharmacology of the
vanilloid receptor. Curr. Opin. Pharmacol. 2, 235–242.
Hwang, S.W., Cho, H., Kwak, J., Lee, S.Y., Kang, C.J., Jung, J., Cho, S.,
Min, K.H., Suh, Y.G., Kim, D., Oh, U., 2000. Direct activation of
capsaicin receptors by products of lipoxygenases: endogenous capsai-
cin-like substances. Proc. Natl. Acad. Sci. U. S. A. 97, 6155–6160.
Ichikawa, H., Sugimoto, T., 2003. The co-expression of VR1 and VRL-1 in
the rat vagal sensory ganglia. Brain Res. 980, 293–296.
Jaggar, S.I., Scott, H.C.F., James, I.F., Rice, A.S.C., 2001. The capsaicin
analogue SDZ 249-665 attenuates the hyperreflexia and referred
hyperalgesia associated with inflammation of the rat urinary bladder.
Pain 89, 229–235.
Jancso ´, N., 1960. Role of the nerve terminals in the mechanism of
inflammatory reactions. Bull. Millard Fillmore Hosp. 7, 53–77.
Jordt, S.E., Julius, D., 2002. Molecular basis for species-specific sensitivity
to bhotQ chili peppers. Cell 108, 421–430.
Jordt, S.E., Tominaga, M., Julius, D., 2000. Acid potentiation of the
capsaicin receptor determined by a key extracellular site. Proc. Natl.
Acad. Sci. U. S. A. 97, 8134–8139.
Jordt, S.E., Bautista, D.M., Chuang, H.H., McKemy, D.D., Zygmunt, P.M.,
Hfgest7tt, E.D., Meng, I.D., Julius, D., 2004. Mustard oils and
cannabinoids excite sensory nerve fibres through the TRP channel
ANKTM1. Nature 427, 260–265.
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
Jung, J., Lee, S.Y., Hwang, S.W., Cho, H., Shin, J., Kang, Y.S., Kim, S.,
Oh, U., 2002. Agonist recognition sites in the cytosolic tails of vanilloid
receptor 1. J. Biol. Chem. 277, 44448–44454.
Jung, J., Shin, J.S., Lee, S.Y., Hwang, S.W., Koo, J., Cho, H., Oh, U., 2004.
Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent
kinaseIIregulatesitsvanilloidbinding. J. Biol. Chem. 279, 7048–7054.
Kagawa, S., Aoi, M., Kubo, Y., Kotani, T., Takeuchi, K., 2003. Stimulation
by capsaicin of duodenal HCO3
vanilloid receptors in rats: comparison with acid-induced HCO3
response. Dig. Dis. Sci. 48, 1850–1856.
Kagaya, M., Lamb, J., Robbins, J., Page, C.P., Spina, D., 2002. Character-
ization of the anandamide induced depolarization of guinea-pig isolated
vagus nerve. Br. J. Pharmacol. 137, 39–48.
Kato, S., Aihara, E., Nakamura, A., Xin, H., Matsui, H., Kohama, K.,
Takeuchi, K., 2003. Expression of vanilloid receptors in rat gastric
epithelial cells: role in cellular protection. Biochem. Pharmacol. 66,
Kawabata, A., Kinoshita, M., Kuroda, R., Kakehi, K., 2002. Capsazepine
partially inhibits neurally mediated gastric mucus secretion following
activation of protease-activated receptor 2. Clin. Exp. Pharmacol.
Physiol. 29, 360–361.
Kawao, N., Ikeda, H., Kitano, T., Kuroda, R., Sekiguchi, F., Kataoka, K.,
Kamanaka, Y., Kawabata, A., 2004. Modulation of capsaicin-evoked
visceral pain and referred hyperalgesia by protease-activated receptors 1
and 2. J. Pharmacol. Sci. 94, 277–285.
Kedei, N., Szabo, T., Lile, J.D., Treanor, J.J., Olah, Z., Iadarola, M.J.,
Blumberg, P.M., 2001. Analysis of the native quaternary structure of
vanilloid receptor 1. J. Biol. Chem. 276, 28613–28619.
Kihara, N., De La Fuente, S.G., Fujino, K., Takahashi, T., Pappas, T.N.,
Mantyh, C.R., 2003. Vanilloid receptor-1 containing primary sensory
neurones mediate dextran sulphate sodium induced colitis in rats. Gut
Kollarik, M., Undem, B.J., 2004. Activation of bronchopulmonary vagal
afferent nerves with bradykinin, acid and vanilloid receptor agonists in
wild-type and TRPV1?/? mice. J. Physiol. (London) 555, 115–123.
Kwak, J., Wang, M.H., Hwang, S.W., Kim, T.Y., Lee, S.Y., Oh, U.,
2000. Intracellular ATP increases capsaicin-activated channel activity
by interacting with nucleotide-binding domains. J. Neurosci. 20,
Laird, J.M., Martinez-Caro, L., Garcia-Nicas, E., Cervero, F., 2001. A new
model of visceral pain and referred hyperalgesia in the mouse. Pain 92,
Lamb, K., Kang, Y.M., Gebhart, G.F., Bielefeldt, K., 2003. Gastric
inflammation triggers hypersensitivity to acid in awake rats. Gastro-
enterology 125, 1410–1418.
Lee, J., Lee, J., Kang, M., Shin, M., Kim, J.M., Kang, S.U., Lim, J.O.,
Choi, H.K., Suh, Y.G., Park, H.G., Oh, U., Kim, H.D., Park, Y.H., Ha,
H.J., Kim, Y.H., Toth, A., Wang, Y., Tran, R., Pearce, L.V., Lundberg,
D.J., Blumberg, P.M., 2003. N-(3-acyloxy-2-benzylpropyl)-NV-[4-
(methylsulfonylamino)benzyl]thiourea analogues: novel potent and
high affinity antagonists and partial antagonists of the vanilloid
receptor. J. Med. Chem. 46, 3116–3126.
Lopshire, J.C., Nicol, G.D., 1998. The cAMP transduction cascade
mediates the prostaglandin E2enhancement of the capsaicin-elicited
current in rat sensory neurons: whole-cell and single-channel studies. J.
Neurosci. 18, 6081–6092.
Lysy, J., Sistiery-Ittah, M., Israelit, Y., Shmueli, A., Strauss-Liviatan, N.,
Mindrul, V., Keret, D., Goldin, E., 2003. Topical capsaicin—a novel
and effective treatment for idiopathic intractable pruritus ani: a
randomised, placebo controlled, crossover study. Gut 52, 1323–1326.
Maggi, C.A., 1995. Tachykinins and calcitonin gene-related peptide
(CGRP) as co-transmitters released from peripheral endings of sensory
nerves. Prog. Neurobiol. 45, 1–98.
Manela, F.D., Ren, J., Gao, J., McGuigan, J.E., Harty, R.F., 1995.
Calcitonin gene-related peptide modulates acid-mediated regulation of
somatostatin and gastrin release from rat antrum. Gastroenterology 109,
?secretion via afferent neurons and
Maubach, K.A., Grundy, D., 1999. The role of prostaglandins in the
bradykinin-induced activation of serosal afferents of the rat jejunum in
vitro. J. Physiol. (London) 515, 277–285.
McDonnell, M.E., Zhang, S.P., Nasser, N., Dubin, A.E., Dax, S.L., 2004. 7-
Hydroxynaphthalen-1-yl-urea and -amide antagonists of human vanil-
loid receptor 1. Bioorg. Med. Chem. Lett. 14, 531–534.
McKemy, D.D., Neuhausser, W.M., Julius, D., 2002. Identification of a
cold receptor reveals a general role for TRP channels in thermosensa-
tion. Nature 416, 52–58.
McLatchie, L.M., Bevan, S., 2001. The effects of pH on the interaction
between capsaicin and the vanilloid receptor in rat dorsal root ganglia
neurons. Br. J. Pharmacol. 132, 899–908.
McVey, D.C., Vigna, S.R., 2001. The capsaicin VR1 receptor mediates
substance P release in toxin A-induced enteritis in rats. Peptides 22,
McVey, D.C., Schmid, P.C., Schmid, H.H., Vigna, S.R., 2003. Endocanna-
binoids induce ileitis in rats via the capsaicin receptor (VR1). J.
Pharmacol. Exp. Ther. 304, 713–722.
Mezey, E., Toth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R.,
Guo, A., Blumberg, P.M., Szallasi, A., 2000. Distribution of mRNA for
vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in
the central nervous system of the rat and human. Proc. Natl. Acad. Sci.
U. S. A. 97, 3655–3660.
Michael, G.J., Priestley, J.V., 1999. Differential expression of the mRNA
for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root
and nodose ganglia and its downregulation by axotomy. J. Neurosci. 19,
Mohapatra, D.P., Nau, C., 2003. Desensitization of capsaicin-activated
dependent protein kinase pathway. J. Biol. Chem. 278, 50080–50090.
Mohapatra, D.P., Wang, S.Y., Wang, G.K., Nau, C., 2003. A tyrosine
residue in TM6 of the vanilloid receptor TRPV1 involved in
desensitization and calcium permeability of capsaicin-activated cur-
rents. Mol. Cell. Neurosci. 23, 314–324.
Moriyama, T., Iida, T., Kobayashi, K., Higashi, T., Fukuoka, T., Tsumura,
H., Leon, C., Suzuki, N., Inoue, K., Gachet, C., Noguchi, K., Tominaga,
M., 2003. Possible involvement of P2Y2 metabotropic receptors in
ATP-induced transient receptor potential vanilloid receptor 1-mediated
thermal hypersensitivity. J. Neurosci. 23, 6058–6062.
Nathan, J.D., Patel, A.A., McVey, D.C., Thomas, J.E., Prpic, V., Vigna,
S.R., Liddle, R.A., 2001. Capsaicin vanilloid receptor-1 mediates
substance P release in experimental pancreatitis. Am. J. Physiol. 281,
Nozawa, Y., Nishihara, K., Yamamoto, A., Nakano, M., Ajioka, H.,
Matsuura, N., 2001. Distribution and characterization of vanilloid
receptors in the rat stomach. Neurosci. Lett. 309, 33–36.
Numazaki, M., Tominaga, T., Toyooka, H., Tominaga, M., 2002. Direct
phosphorylation of capsaicin receptor VR1 by protein kinase C-e
and identification of two target serine residues. J. Biol. Chem. 277,
Numazaki, M., Tominaga, T., Takeuchi, K., Murayama, N., Toyooka,
H., Tominaga, M., 2003. Structural determinant of TRPV1 desensi-
tization interacts with calmodulin. Proc. Natl. Acad. Sci. U. S. A. 100,
Olah, Z., Karai, L., Iadarola, M.J., 2002. Protein kinase C-a is required for
vanilloid receptor 1 activation. Evidence for multiple signaling path-
ways. J. Biol. Chem. 277, 35752–35759.
Patapoutian, A., Peier, A.M., Story, G.M., Viswanath, V., 2003. Ther-
moTRP channels and beyond: mechanisms of temperature sensation.
Nat. Rev., Neurosci. 4, 529–539.
Patterson, L.M., Zheng, H., Ward, S.M., Berthoud, H.R., 2003. Vanilloid
receptor (VR1) expression in vagal afferent neurons innervating the
gastrointestinal tract. Cell Tissue Res. 311, 277–287.
Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A.,
Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., Bevan, S.,
Patapoutian, A., 2002. A TRP channel that senses cold stimuli and
menthol. Cell 108, 705–715.
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241
Perry, M.J., Lawson, S.N., 1998. Differences in expression of oligosac- Download full-text
charides, neuropeptides, carbonic anhydrase and neurofilament in rat
primary afferent neurons retrogradely labelled via skin, muscle or
visceral nerves. Neuroscience 85, 293–310.
Plourde, V., St.-Pierre, S., Quirion, R., 1997. Calcitonin gene-related
peptide in viscerosensitive response to colorectal distension in rats. Am.
J. Physiol. 273, G191–G196.
Poonyachoti, S., Kulkarni-Narla, A., Brown, D.R., 2002. Chemical coding
of neurons expressing delta- and kappa-opioid receptor and type I
vanilloid receptor immunoreactivities in the porcine ileum. Cell Tissue
Res. 307, 23–33.
Premkumar, L.S., Ahern, G.P., 2000. Induction of vanilloid receptor
channel activity by protein kinase C. Nature 408, 985–990.
Premkumar, L.S., Qi, Z.H., Van Buren, J., Raisinghani, M., 2004.
Enhancement of potency and efficacy of NADA by PKC-mediated
phosphorylation of vanilloid receptor. J. Neurophysiol. 91, 1442–1449.
Prescott, E.D., Julius, D., 2003. A modular PIP2 binding site as a
determinant of capsaicin receptor sensitivity. Science 300, 1284–1288.
Reeh, P.W., Pethf, G., 2000. Nociceptor excitation by thermal sensitiza-
tion—a hypothesis. Prog. Brain Res. 129, 39–50.
Ritter, S., Dinh, T.T., 1988. Capsaicin-induced neuronal degeneration:
silver impregnation of cell bodies, axons, and terminals in the central
nervous system of the adult rat. J. Comp. Neurol. 271, 79–90.
Robinson, D.R., McNaughton, P.A., Evans, M.L., Hicks, G.A., 2004.
Characterization of the primary spinal afferent innervation of the
mouse colon using retrograde labelling. Neurogastroenterol. Motil. 16,
Rosenbaum, T., Gordon-Shaag, A., Munari, M., Gordon, S.E., 2004. Ca2+/
calmodulin modulates TRPV1 activation by capsaicin. J. Gen. Physiol.
Ross, R.A., 2003. Anandamide and vanilloid TRPV1 receptors. Br. J.
Pharmacol. 140, 790–801.
Sanchez, J.F., Krause, J.E., Cortright, D.N., 2001. The distribution and
regulation of vanilloid receptor VR1 and VR1 5V splice variant RNA
expression in rat. Neuroscience 107, 373–381.
Savidge, J., Davis, C., Shah, K., Colley, S., Phillips, E., Ranasinghe, S.,
Winter, J., Kotsonis, P., Rang, H., McIntyre, P., 2002. Cloning and
functional characterization of the guinea pig vanilloid receptor 1.
Neuropharmacology 43, 450–456.
Schicho, R., Florian, W., Liebmann, I., Holzer, P., Lippe, I.T., 2004.
Increased expression of TRPV1 receptor in dorsal root ganglia by acid
insult of the rat gastric mucosa. Eur. J. Neurosci. 19, 1811–1818.
Schmidt, B., Hammer, J., Holzer, P., Hammer, H.F., 2004. Chemical
nociception in the jejunum induced by capsaicin. Gut 53, 1109–1116.
Schuligoi, R., Jocic, M., Heinemann, A., Schfninkle, E., Pabst, M.A.,
Holzer, P., 1998. Gastric acid-evoked c-fos messenger RNA expression
in rat brainstem is signaled by capsaicin-resistant vagal afferents.
Gastroenterology 115, 649–660.
Shin, J., Cho, H., Hwang, S.W., Jung, J., Shin, C.Y., Lee, S.Y., Kim, S.H.,
Lee, M.G., Choi, Y.H., Kim, J., Haber, N.A., Reichling, D.B., Khasar,
S., Levine, J.D., Oh, U., 2002. Bradykinin-12-lipoxygenase-VR1
signaling pathway for inflammatory hyperalgesia. Proc. Natl. Acad.
Sci. U. S. A. 99, 10150–10155.
Smart, D., Jerman, J.C., Gunthorpe, M.J., Brough, S.J., Ranson, J., Cairns,
W., Hayes, P.D., Randall, A.D., Davis, J.B., 2001. Characterisation
using FLIPR of human vanilloid VR1 receptor pharmacology. Eur. J.
Pharmacol. 417, 51–58.
Smith, G.D., Gunthorpe, M.J., Kelsell, R.E., Hayes, P.D., Reilly, P., Facer,
P., Wright, J.E., Jerman, J.C., Walhin, J.P., Ooi, L., Egerton, J., Charles,
K.J., Smart, D., Randall, A.D., Anand, P., Davis, J.B., 2002. TRPV3 is
a temperature-sensitive vanilloid receptor-like protein. Nature 418,
Su, X., Wachtel, R.E., Gebhart, G.F., 1999. Capsaicin sensitivity and
voltage-gated sodium currents in colon sensory neurons from rat dorsal
root ganglia. Am. J. Physiol. 277, G1180–G1188.
Suh, Y.G., Lee, Y.S., Min, K.H., Park, O.H., Seung, H.S., Kim, H.D., Park,
H.G., Choi, J., Lee, J., Kang, S.W., Oh, U.T., Koo, J.Y., Joo, Y.H., Kim,
S.Y., Kim, J.K., Park, Y.H., 2003. Novel non-vanilloid VR1 antagonist
of high analgesic effects and its structural requirement for VR1
antagonistic effects. Bioorg. Med. Chem. Lett. 13, 4389–4393.
Sun, Q., Tafesse, L., Islam, K., Zhou, X., Victory, S.F., Zhang, C.,
Hachicha, M., Schmid, L.A., Patel, A., Rotshteyn, Y., Valenzano, K.J.,
Kyle, D.J., 2003. 4-(2-Pyridyl)piperazine-1-carboxamides: potent vanil-
loid receptor 1 antagonists. Bioorg. Med. Chem. Lett. 13, 3611–3616.
Suzuki, M., Mizuno, A., Kodaira, K., Imai, M., 2003. Impaired pressure
sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668.
Szallasi, A., Blumberg, P.M., 1999. Vanilloid (capsaicin) receptors and
mechanisms. Pharmacol. Rev. 51, 159–212.
Szolcsa ´nyi, J., 1982. Capsaicin type pungent agents producing pyrexia. In:
Milton, A.S. (Ed.), Pyretics and Antipyretics, Handbook of Exper-
imental Pharmacology8 vol. 60. Springer, Berlin, pp. 437–478.
Szolcsa ´nyi, J., Jancso ´-Ga ´bor, A., 1975. Sensory effects of capsaicin
congeners: I. Relationship between chemical structure and pain-
producing potency of pungent agents. Drug Res. 25, 1877–1881.
Takaki, M., Nakayama, S., 1989. Effects of capsaicin on myenteric neurons
of the guinea pig ileum. Neurosci. Lett. 105, 125–130.
Tashima, K., Nakashima, M., Kagawa, S., Kato, S., Takeuchi, K., 2002.
Gastric hyperemic response induced by acid back-diffusion in rat
stomachs following barrier disruption—relation to vanilloid type-1
receptors. Med. Sci. Monit. 8, BR157–BR163.
Tominaga, M., Caterina, M., Malmberg, A.B., Rosen, T.A., Gilbert, H.,
Skinner, K., Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The
cloned capsaicin receptor integrates multiple pain-producing stimuli.
Neuron 21, 531–543.
Trevisani, M., Smart, D., Gunthorpe, M.J., Tognetto, M., Barbieri, M.,
Campi, B., Amadesi, S., Gray, J., Jerman, J.C., Brough, S.J., Owen, D.,
Smith, G.D., Randall, A.D., Harrison, S., Bianchi, A., Davis, J.B.,
Geppetti, P., 2002. Ethanol elicits and potentiates nociceptor responses
via the vanilloid receptor-1. Nat. Neurosci. 5, 546–551.
Urban, L., Campbell, E.A., Panesar, M., Patel, S., Chaudhry, N., Kane,
S., Buchheit, K., Sandells, B., James, I.F., 2000. In vivo pharmacol-
ogy of SDZ 249-665, a novel, non-pungent capsaicin analogue. Pain
Vellani, V., Mapplebeck, S., Moriondo, A., Davis, J.B., McNaughton, P.A.,
2001. Protein kinase C activation potentiates gating of the vanilloid
receptor VR1 by capsaicin, protons, heat and anandamide. J. Physiol.
(London) 534, 813–825.
Wahl, P., Foged, C., Tullin, S., Thomsen, C., 2001. Iodo-resiniferatoxin, a
new potent vanilloid receptor antagonist. Mol. Pharmacol. 59, 9–15.
Ward, S.M., Bayguinov, J., Won, K.J., Grundy, D., Berthoud, H.R., 2003.
Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract.
J. Comp. Neurol. 465, 121–135.
Welch, J.M., Simon, S.A., Reinhart, P.H., 2000. The activation mechanism
of rat vanilloid receptor 1 by capsaicin involves the pore domain and
differs from the activation by either acid or heat. Proc. Natl. Acad. Sci.
U. S. A. 97, 13889–13894.
Yiangou, Y., Facer, P., Dyer, N.H., Chan, C.L., Knowles, C., Williams,
N.S., Anand, P., 2001. Vanilloid receptor 1 immunoreactivity in
inflamed human bowel. Lancet 357, 1338–1339.
Zhang, Y., Hoon, M.A., Chandrashekar, J., Mueller, K.L., Cook, B., Wu,
D., Zuker, C.S., Ryba, N.J., 2003. Coding of sweet, bitter, and umami
tastes: different receptor cells sharing similar signaling pathways. Cell
Zhang, L., Jones, S., Brody, K., Costa, M., Brookes, S.J., 2004.
Thermosensitive transient receptor potential channels in vagal afferent
neurons of the mouse. Am. J. Physiol. 286, G983–G991.
Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H.-H., Sbg3rd, M.,
Di Marzo, V., Julius, D., Hfgest7tt, E.D., 1999. Vanilloid receptors on
sensory nerves mediate the vasodilator action of anandamide. Nature
P. Holzer / European Journal of Pharmacology 500 (2004) 231–241