PAIN 141 (2009) 191–209

www.elsevier.com/locate/pain

Review

Basic and clinical aspects of gastrointestinal pain

Charles H. Knowles a,*, Qasim Aziz b
a
Neurogastroenterology Group, Centres for Academic Surgery, Barts and the London NHS Trust and the Homerton, University NHS Foundation Trust,
3rd Floor Alexandra Wing, Royal London Hospital, London E1 1BB, UK
b
Gastroenterology, Wingate Institute of Neurogastroenterology, Barts and the London, Queen Mary’s School of Medicine and Dentistry, Whitechapel, London, UK

a r t i c l e i n f o a b s t r a c t

Article history: The gastrointestinal (GI) tract is a system of organs within multicellular animals which facilitates the
Received 31 July 2008 ingestion, digestion, and absorption of food with subsequent defecation of waste. A complex arrangement
Received in revised form 29 September 2008 of nerves and ancillary cells contributes to the sensorimotor apparatus required to subserve such essen-
Accepted 3 December 2008
tial functions that are with the exception of the extreme upper and lower ends of the GI tract normally
subconscious. However, it also has the potential to provide conscious awareness of injury. Although this
function can be protective, when dysregulated, particularly on a chronic basis, the same system can lead
Keywords:
to considerable morbidity. The anatomical and molecular basis of gastrointestinal nociception, conditions
Visceral pain
Gastrointestinal pain
associated with chronic unexplained visceral pain, and developments in treatment are presented in this
Nociception review.
Visceral hypersensitivity ! 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Sensitisation

Grant support: C.H.K. is supported by the Higher Education tential to provide conscious awareness of injury. From a teleologic
Funding Council of England and the Pseudo-obstruction Research perspective such an arrangement may have been advantageous,
Trust. Q.A. is supported by Medical Research Council Career Estab- and in certain current circumstances continues to be protective.
lishment Award and the Rosetrees Trust. However, when dysregulated, particularly on a chronic basis, the
same system can lead to considerable morbidity.
1. Introduction
1.1. Scope
The gastrointestinal (GI) tract is a system of organs within mul-
ticellular animals which facilitates the ingestion, digestion, and The review is limited to areas that are of most interest from ba-
absorption of food with subsequent defecation of waste. A complex sic science or clinical standpoints, particularly where the former
arrangement of nerves and ancillary cells contributes to the senso- informs the latter and where there are important differences from
rimotor apparatus required to subserve such essential functions somatic pain. As the title suggests, where possible, the review will
that are with the exception of the extreme upper and lower ends focus on human research, however, it necessarily draws much from
of the GI tract normally subconscious. However, it also has the po- observations in experimental animals. It also only considers the
luminal component of the digestive system and not the conditions
affecting solid ancillary organs, e.g. chronic pancreatitis. Of special
note, the review has attempted to pull away from the sole discus-
Abbreviations: ACC, anterior cingulated cortex; ASIC, acid-sensing ion channel;
ATP, adenosine triphosphate; ANS, autonomic nervous system; CGRP, calcitonin sion of the currently fashionable and repetitively reviewed
gene-related peptide; CCK, cholecystokinin; CRH, corticotrophin-releasing hor- [10,11,127,164] area of visceral hypersensitivity. The review is or-
mone; CS, central sensitisation; ENS, enteric nervous system; 5HT, 5-hydroxy- dered on the basis of a progression from basic to clinical with the
trypamine; FGID, functional gastrointestinal disorders; GI, gastrointestinal; GINMD, following structure:
gastrointestinal neuromuscular disease; GCPR, G-protein-coupled receptor; HAP,
hypothalamo–pituitary axis; IB4, isolectin-B4; IGLE, intraganglionic laminar end-
ing; NGF, nerve growth factor; LC, locus cereleus; NDMA, N-methyl-D-aspartate; 1. Anatomical basis of GI nociception (spinal, vagal pathways and
NK, neurokinin; PAG, peri-aquaductal grey; PG, prostaglandin; PAR, the enteric nervous system).
protease-activated receptor; SP, substance-P; SNS, sacral nerve stimulation; SST, 2. Molecular basis of GI nociception (peripheral and central signal-
somatostain; TTX, tetrodotoxin; TRP, transient receptor potential; VH, visceral
ling and sensitisation).
hypersensitivity; VGSC, voltage-gated sodium channel.
* Corresponding author. Tel.: +44 207 377 7449; fax: +44 207 377 7346. 3. Modulatory influences on GI nociception (descending neural,
E-mail address: c.h.knowles@qmul.ac.uk (C.H. Knowles). autonomic and hypothalamo–pituitary axis).

0304-3959/$34.00 ! 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2008.12.011
192 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

4. Clinical syndromes characterised by chronic unexplained GI and respond only to noxious intensities of organ distension and
pain: are thus considered mechanonociceptors [224,225]. Aside from
a. Clinical overview and importance. innervating the gut wall, such afferents have many endings located
b. Applied pathophysiology. at intensely mechanosensitive sites in the mesentery and serosa
5. Treatment of chronic GI pain. [45,235]. They are also chemosensitive, responding directly to a
variety of inflammatory mediators [148] and may mediate well-
characterised responses to ischaemia at sites near mesenteric ves-
2. The anatomical basis of GI nociception sels [45,147,175]. (3) Silent nociceptors, which only develop activ-
ity and mechanosensitivity after exposure to inflammatory
2.1. General organisation mediators. They are assumed but not proven to play a role in the
viscera similar to that observed in somatic pain [147].
Important differences exist between the organisation of the so- Unlike autonomic efferents that synapse in coeliac, hypogas-
matic nervous system and that of the viscera reflecting the com- tric plexuses, or sympathetic ganglia, first-order spinal afferents
plex embryology of the GI tract. These variations represent the traverse paravertebral and prevertebral ganglia (although some
functional fusion of migrating neural crest cells that form intrinsic give collateral branches to the ganglia that mediate local reflex
ganglionic plexuses and vagal neurons [47] with extrinsic nerves changes including blood flow [114]) to synapse like somatic
that also develop from the neural crest, but which migrate in re- afferents in the dorsal horn with cell bodies in the dorsal root
sponse to similar cues as blood vessels in the mesentery [51]. In ganglia. The detailed central neuroanatomy of visceral afferents
contrast to somatic nociception, the situation in the gut is therefore has been most extensively studied in rodents where these fibres
complicated by the presence of two extrinsic innervations (vagal constitute only 7–10% of all afferent inflow into the cord, but
and spinal), as well as of numerous intrinsic neurons. The latter have a widespread distribution in laminae I, II, V and X
are particularly important because (1) they complicate the identi- [104,179]. Whilst the spinal levels of sympathetic preganglionic
fication of nociceptors, particularly in the mucosa, and (2) they efferents are well established between T1 and L2, the levels of
may contribute to the transduction of pain. afferents are spread across a broad range of DRGs with peak dis-
tributions for different organs. As a result, a generalised, overlap-
ping, and viscerotropic distribution of spinal afferent fibre cell
2.2. GI nociceptors bodies exists [24] between C1 (upper oesophagus) and S4 (rec-
tum and bladder) (Fig. 2a). This and the relatively small propor-
In respect of extrinsic afferents, the division of the autonomic tion of cell bodies assigned to the viscera are factors that
nervous system into sympathetic and parasympathetic divisions probably contribute to the poor localisation of visceral versus so-
is a misnomer that only accurately refers to efferent functions matic pain [56,225]. The viscerosomatic convergence at the level
[27]. Rather, the most useful broad anatomical and functional divi- of the dorsal horn of the spinal cord accounts for the referral
sion is into that of vagal and spinal visceral afferent fibres [95,104]. experienced with visceral pain.
The latter may be further divided into splanchnic and pelvic affer- Second-order neurons project to the brain through the spi-
ents, with these following the paths of sympathetic and parasym- noreticular, spinomesencephalic, spinohypothalamic and spino-
pathetic nerves, respectively. Vagal and spinal nerves have endings thalamic tracts [9], all of which lie in the anterolateral quadrant
in all layers of the gut wall (Fig. 1), which, unlike some somatic of the spinal cord (Fig. 2b). Whilst the first three of these tracts
sensory nerve endings, lack defined anatomical specification such mainly activate largely unconscious and/or automatic responses
as encapsulation. Axons are in the most part unmyelinated (C fi- to visceral sensory input including alterations in emotion and
bres) with a minority having thin myelination (Ad fibres). It is gen- behaviour, the latter transmits conscious sensation by its projec-
erally held that vagal afferents have a much lesser role in tion via sensory nuclei of the thalamus to the somatosensory cor-
nociception than spinal afferents [58], however, the vagus may tex (SI/II lateral pain system), anterior cingulate cortex (ACC)
have some role in pathophysiologic conditions [95]. The reader is (medial pain system) and the insula [9,10]. Whereas the main
reminded that much of the following description relates to exper- function of the lateral pain system is to provide intensity and
imental animals. localisation of the stimulus, the medial system modulates affec-
tive pain behaviour with stimulation of important autonomic
and descending inhibitory pathways (see below). The insula and
2.3. Spinal GI nociception other regions such as the orbital prefrontal cortex have important
roles in sensory integration and in the higher control of auto-
Spinal visceral afferents represent 10–20% of nerve fibres in nomic visceromotor and behavioural responses. This widespread
splanchnic nerves, and project to all layers of the gut wall including distribution of afferent pathways to areas beyond those required
the serosa and mesenteric attachments where they terminate as for localisation alone may account for the strong emotional com-
bare nerve endings [36]. Combined tracer and electrophysiologic ponent of visceral pain (further discussed below) and differences
studies have placed these fibres as the main source of visceral noci- between patients with chronic visceral pain and controls in the
ception with single-unit recordings from various gut regions dem- degree of activation of these pain areas [170,202]. A further vis-
onstrating that high-threshold fibres are almost exclusively of ceral pain pathway has also been established in the dorsal col-
spinal origin [184]. In addition to mucosal endings [151], which umns of rats and primates [6,7,8] which passes via ipsilateral
may participate particularly in chemonociception, there are three dorsal column nuclei [6] to the contralateral ventroposterolateral
further neurophysiologically defined groups of spinal mechanosen- nucleus of the thalamus [6]. In humans, this pathway may also be
sitive afferents: (1) Tonic (or wide dynamic range) mechanorecep- important, although this is currently based on limited evidence
tors which have tonic levels of resting activity and respond like [155].
vagal muscle afferents linearly with rising wall tension starting The transmission of nociceptive information from visceral
at low thresholds [224,225]. In addition to signalling sensations, spinal afferents can be modulated in ways similar to that from so-
such as fullness, these continue to be activated well into the nox- matic afferents with ‘gating’ influences from converging visceroso-
ious range and may thus act as mechanonociceptors. (2) High matic nociceptive and non-nociceptive neurons. Pain thresholds in
threshold (or phasic) mechanoreceptors have low resting activity the viscera are increased by viscerosomatic inputs with transient
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 193

Fig. 1. Schematic representation of nerve endings in the gut wall. Endings are located in all gut layers, however, based on current evidence, those indicated are most likely to
play a role in nociception with others, particularly those arising from vagal and pelvic nerves (intraganglionic laminar endings and intramuscular arrays) having no currently
proven role.

inhibition of transmission demonstrated [236]. This may account in which application of an acute aversive stimulus provides tempo-
for clinical phenomena such as the episodic nature of colic [10], rary relief of chronic and recurrent pain [245]. Recent studies sug-
the efficacious rubbing of ‘a stitch’, and the application of hot water gest that some patients with chronic abdominal pain demonstrate
bottles on the abdominal wall by patients (with subsequent ery- abnormal perceptual responses and brain activation patterns to
thema ab igme). Some neurons in the dorsal horn of the spinal cord rectal pain when it is associated with concomitant heterotopic
are also strongly inhibited when a nociceptive stimulus is applied stimulation using ice water immersion of the foot, which is known
to any part of the body, distinct from their excitatory receptive to activate this system [255,256]. In a feline model of visceral pain,
fields. This neurophysiologic phenomenon [140] underlies the such neurons can also refine ascending information to assist in in-
long-established clinical phenomenon of counter-irritation [216], jury localisation [88].
194 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

Fig. 2. (a) Schematic representation of the viscerotropic distribution of spinal afferent fibre innervation of the GI tract on the basis of retrograde tracer studies in experimental
animals. The bars represent DRGs labelled with tracer from each organ with peak distributions (dark shade) and ranges (white) shown for each. Key: E, oesophagus. Note:
although human studies suggest (like the bladder) a rectal afferent innervation to L5–S4, the anatomical lack of distinction of this organ from the colon in small mammals
means that direct tracer data are unavailable. Adapted from Beyak et al. [24]. (b) Main central connections for GI pain pathways. Key: pACC, perigenual anterior cingulated
cortex; MCC, mid-cingulate cortex. For clarity, spinomesencephalic and spinohypothalamic pathways have been omitted (reproduced with permission from Matthews and
Aziz. Postgrad Med J 2005).

2.4. Pelvic nerves to segments S2–4 in humans (although this is species dependent
L5–S5), with cell bodies in the DRGs at these levels. Approximately
Although grouped with spinal afferents, these neurons require one-third of pelvic nerves are afferents [135], principally of the Ad
special mention. Like the upper GI tract that has a dual innervation and C fibre types [90]. At a peripheral morphologic and functional
(vagal and spinal), the lower colon and rectum also receive an level, these have more in common with vagal endings (below),
innervation that is anatomically independent of splanchnic neu- being largely mechanosensitive [42,152] rather than nociceptive,
rons, but which similarly projects to the sacral spinal cord. Such and also have a population of intraganglionic laminar endings
pelvic nerves pass only through the pelvic plexuses and nerves, [152,183]. To what extent such endings participate in pain trans-
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 195

mission is currently not well studied but is of clinical importance uli [93]. To avoid confusion, these are now described as intrinsic
in pelvic pain. The proximal extent of their influence as with motor primary afferent neurons (IPANs) [126] rather than as intrinsic
nerves [128,219] is unclear and likely to be species dependent [60]. ‘sensory’ neurons [136]. Morphologically, IPANs have a Dogiel type
II appearance [93] with multiple dendrites and a single axon, and
2.5. The role of the vagus in nociception demonstrate characteristic ‘after hyperpolarisation’ neurophysio-
logical properties caused by three inward somal currents. These in-
Approximately 50,000 (98% unmyelinated) vagal afferents sup- clude a tetrodotoxin (TTX)-insensitive Na+ current consistent with
ply the GIT [225]. Single-unit recordings in experimental animals the proven expression of the nociceptive ion channel Nav1.9 [207].
demonstrate that unlike spinal afferents, the vagus consists almost Indeed, it is now well established that IPANs can be damage sens-
entirely of low-threshold fibres [184], and conventional wisdom ing and respond to noxious luminal conditions by mediating pow-
has thus placed the vagus as a sensor of primarily physiologic erful local reflexes to expel organisms/toxic chemicals from the GI
non-noxious stimuli (satiety, nausea, fullness, etc.). This is sup- tract [4]. This finding is also in keeping with their binding of the
ported by vagal ablation studies, where levels of activity in the nociceptor-associated plant lectin IB4 [111]. Whether such neu-
noxious distension range remain unchanged [211], by early human rons, half of which project to the myenteric plexus of their own
studies [252], and by clinical observations relating to the affects of and adjacent ganglia [92], can participate in signalling to extrinsic
vagal stimulation [223]. Outside the physiological range, studies afferents (perhaps by interactions with IGLEs) and thence con-
have, however, demonstrated that noxious gastric distension is scious pain, remains an attractive but yet unproven hypothesis
associated with continued firing of a subgroup of low-activation [35]; and one that may prove difficult to establish. Their role in
threshold neurons termed ‘wide dynamic sensitivity’ afferents peripheral sensitisation is discussed below.
[185]. In relation to specific types of vagal nerve endings, mucosal
receptors have rapidly adapting neurophysiological responses to
2.7. Summary box
fine stroking and do not respond to distension [105,187,189] and
at basal conditions are thus unlikely to have a significant mech-
anonociceptive role. Chemosensitivity to a wide range of intralu-
! Current information suggests that GI nociception is mediated
minal chemical and osmotic stimuli is their main role, as well as
almost entirely by spinal visceral afferents.
mediation of some unpleasant sensations such as nausea and vom-
! A combination of chemo- and mechano-nociceptors, especially
iting [25,27], with their further activation by inflammatory media-
spinal mesenteric and serosal nerve endings, mediates acute
tors implicating them as ‘silent’ chemonociceptors in disease states
pain as occurs with significant distension or ischaemia. Mucosal
[142,233]. Two further specialised groups of endings terminate
endings probably have a greater role after sensitisation such as
deeper in the bowel wall. The first group, intramuscular arrays,
occurs in inflammatory states.
consists of two or more parallel processes originating from a single
! The roles of the vagus and intrinsic afferents either alone or in
axon [26] and is unlikely to have major roles in nociception,
combination in pain transmission, especially that from the
responding to low levels of distension or contraction of the gut
mucosa, are receiving increasing attention.
wall with a slowly adapting, linear relationship to wall tension
within the physiological range [37]. The second group, intragangl-
ionic laminar endings (IGLEs) [180], terminates as a cluster of mul-
tiple endings which encapsulate a myenteric ganglion. A 3. The molecular basis of gastrointestinal pain
combination of fast axonal labelling techniques with electrophysi-
ological characterisation has shown that these act as mechanosen- It has been noted that spinal visceral afferents particularly those
sors in response to low intensity shearing forces between circular arising from the mesentery are the main source of GI nociception.
and longitudinal muscle [152,269] but have no established role There is no particular reason to suppose that such neurons differ
in nociception. Whilst they clearly (by close apposition) also have greatly from their somatic counterparts, having similar ontogeny
potential to respond to intraganglionic release of mediators by (although less studied) and basic morphology (bare nerve endings,
intrinsic neurons termed recently as ‘intrinsic–extrinsic ‘crosstalk’ unmyelinated or thinly myelinated axon, pseudo-unipolar with
(below) [35], a true ‘sensory’ role for this interaction requires fur- cell bodies in the DRG and first synapse in the dorsal horn). In
ther proof. terms of mechanisms of pain transmission, it is therefore not
Vagal afferents have their cell bodies in the inferior vagal gan- unreasonable to consider the evidence for similar molecular events
glion in humans, and mainly in nodose ganglion in animals, thence in visceral nociception. The main experimental methods used to
projecting centrally to the brainstem where their processes termi- determine these events are in general limited to inflammatory pain
nate in the nucleus of the tractus solitarii. These neurons in turn and are listed in Table 1.
project to the thalamus (mostly via the parabrachial nucleus) and
thereafter to specific areas of the cortex sometimes described as 3.1. Peripheral visceral sensory signalling and sensitisation (Fig. 3)
the ‘visceral sensory neuromatrix [10]’. In addition, vagal afferents
project directly to other areas such as the hypothalamus, amyg- The peripheral terminals of nociceptors confer much of their
dala, peri-aquaductal grey (PAG) and locus coeruleus (LC) regulat- specialised properties. In common with other afferents, generator
ing emotional, autonomic and behavioural responses. potentials are produced by opening voltage-gated sodium channels
in response to a depolarising stimulus, and are terminated by a
2.6. The role of the enteric nervous system in nociception combination of time, voltage-gated inactivation of these channels
and opening of a voltage-sensitive outward potassium conduc-
It is clear that neurons intrinsic to the gut wall cannot convey tance [100]. In somatic afferents, Nav1.7 carries much of the TTX-
conscious sensation and strictly speaking therefore should not be S (sensitive) current and appears to be the critical switch for mech-
termed ‘sensory’. Nevertheless, of the now 16 functionally defined anonociception [176]. This appears to also hold true for visceral
classes (in the guinea pig at least) of neurons whose cell bodies are afferents with similar TTX-S currents recorded from DRG and no-
intrinsic to the gut wall, approximately 20% of the half billion neu- dose ganglia of experimental animals following retrograde axonal
rons present participate in the afferent limb of local reflexes labelling from various GI organs [34,229,232]. TTX-R (resistant)
including peristalsis in response to chemical and mechanical stim- currents are localised preferentially to small, unmyelinated
196 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

Table 1
Experimental methods used in determining molecular mechanisms of visceral nociception.

! Studies on isolated (cultured) cells (in vitro) (Ca2+ imaging, patch clamping and intracellular recordings)
! Electrophysiologic studies of afferent nerve fibres ± sensitisation
! Studies of provoked rodent pseudo-affective behaviours and visceromotor responses following chemical or microbial-induced luminal inflammation and
" Modulation of these responses by pharmacologic blockade (selective antagonists)/gene knock-out or knock-down using siRNA)

! Tissue (protein and RNA) expression studies of molecular targets (following sacrifice: gut, DRG, nodose, spinal cord)
! Studies of protein expression in full-thickness GI tissues from patients with proven inflammatory pain conditions, e.g. inflammatory bowel disease
! Studies of human healthy volunteers exposed to intraluminal inflammatory stimuli with subsequent specific pharmacologic manipulation

nociceptor-like fibres with the predominant channels being Nav1.8 creased at reduced extracellular pH [181], as well as contributing
and 1.9. Both have specialised biophysical properties that may to mechanosensation [264].
complement each other’s function, with Nav1.9 influencing overall
membrane excitability and possibly amplifying small stimuli 3.2. Peripheral sensitisation
[5,65]. Nav1.8-like currents are present in most DRGs innervating
the viscera [34,232], whereas Nav1.9 is preferentially expressed Peripheral sensitisation represents a form of stimulus-evoked
in a subset of GDNF-sensitive, IB4-reactive small nociceptors that nociceptor plasticity in which more prolonged stimulation, partic-
are less populous in visceral DRGs [204], but have been noted to ularly in the context of injury or inflammation, leads to a change in
also be expressed by intrinsic neurons [186,207] whose role in the chemical milieu that permits nociceptor firing at lower thresh-
nociception remains to be established. The further relevance of so- olds than that required for an acute noxious stimulus, leading to
dium channels to visceral pain is illustrated by the observation that the phenomenon of decreased pain thresholds at the site of injury
point mutations in the SCN9A gene (encoding Nav1.7) lead to both (primary hyperalgesia). There is abundant experimental and clini-
somatic (primary erythermalgia) and visceral (familial rectal pain cal evidence to suggest that this occurs in the inflamed GI tract
(FRP)) syndromes by increasing channel activity [208]. In terms (oesophagus to colon) with several studies directly demonstrating
of rectifying currents, both IA (rapidly inactivating) and IK (delayed electrophysiologic endpoints, i.e. increases in TTX-R and TTX-S cur-
rectifier) currents have been demonstrated in GI extrinsic sensory rents and reductions in restorative potassium currents resulting in
neurons, including stomach [67] and ileum [229]. A discussion of changes favouring nociceptor excitability [28,33,34,67,229]. Such
further currents, e.g. hyperpolarisation (IH), and channels, e.g. cal- sensitisers include kinins, e.g. bradykinin; biogenic amines, e.g.
cium-activated potassium channels and voltage-gated calcium histamine and 5HT; prostanoids, e.g. PGE2 growth factors (NGF
channels, can be found elsewhere [27]. and GDNF); proteases; chemokines and cytokines as well as reduc-
Transduction of noxious GI stimuli into generator currents at a tions in pH and increases in ATP [10,104]. Whilst some nociceptor
molecular level, in common with somatic nociceptors, requires the sensitisers can mediate their effects directly by altering receptor
expression of ion channels that are able to respond with a high kinetics of VGSCs, e.g. PGE2 [101], and cation channels, e.g. low
threshold to particular changes in the mechanical, chemical and pH and ATP [117], the majority of the effects are induced by bind-
thermal environment [197]. The identification of such transducers, ing to a number of specific G-protein coupled receptors (GPCRs) on
starting with TRPV1 [53], over the past 10 years has been an area of the nociceptor membrane with subsequent activation of multiple
major scientific progress and one that may eventually translate intracellular signalling pathways including protein, PI3 and MAP
into therapy (below). Studies in heterologous expression systems kinases (reviewed: [262]). Such signalling mechanisms thence
and knock-out mice have led to an ever expanding list of non- have the secondary effect of reducing transduction thresholds of
selective cation, potassium and ligand-gated ion channels with cation channels, e.g. TRP channels, usually by phosphorylation
functions in somatic pain [262]. In the GI tract, three groups have [31]. In keeping with a role in GI nociception, expression of all rel-
been well characterised: (1) Transient receptor potential (TRP) evant GPCRs, e.g. Bradykinin 2 (B2) receptors [43], PG receptors
channels are a large family of highly conserved channels that sub- [159], histamine receptors [212], 5HT receptors [96], TrK A [73],
serve sensory functions as diverse as hearing and pain [197]. Sev- Ret [84] and PAR2 [55] receptors, has been demonstrated in several
eral are known to be expressed by extrinsic spinal and vagal classes of GI afferents with a further subset of GPCRs having ac-
afferents as well as by intrinsic neurons throughout the GI tract tions that modulate sensitisation by inhibition, e.g. somatostatin
of experimental animals [15,44,246] and man [161,268]. There is [206], some opioids [190] and CB1 receptors [124], with possible
good experimental evidence to suggest that TRPV1, TRPV4, and re- relevance to therapy.
cently TRPA1 have roles, to a varying degree, in GI chemo-, thermo- Sensitisation can be further augmented by a number of interac-
and mechano-nociception [32,44,53,72] and that TRPV4 may di- tions with adjacent cells including epithelia and inflammatory
rectly transduce mechanosensation [145]. With special reference cells. Multi- (at least tri-) directional interactions with mast cells
to the GI tract, many of these channels also contribute to the ‘tast- and lymphocytes underlie processes such as neurogenic inflamma-
ing’ of a variety of potentially noxious (this being itself a question tion in which biogenic amines stimulate the release of neuropep-
of personal taste!) foodstuffs such as chilli, menthol, garlic, mus- tides, such as substance P (SP) and calcitonin gene-related
tard, horseradish and some herbs [23,53,153,265]. (2) Acid-sensing peptide (CGRP), with these then stimulating NGF release from sev-
ion channels (ASIC 1–3) are members of a voltage-insensitive, eral target cell types [143]. NGF, in addition to several other
amiloride-sensitive epithelial Na+ channel/degenerin family of cat- inflammatory mediators described (in the somatic nervous sys-
ion channels [244] that are sensitive to pH ranges 6–7 and are, tem), can promote a phenotypic switch to further sensitisation
with albeit some conflicting evidence [77], considered to have di- by retrograde signalling to the nociceptor soma and thence up-reg-
rect roles singly or as a ‘transduction complex’ in GI mechanosen- ulation (by a number of transcriptional mechanisms) of neuropep-
sation [188] as well as in chemonociception from luminal acid tide and particularly cation, e.g. TRPV [267] and VGSC [86],
[127]. And (3) P2X purinoceptors (P2X1–9) are ligand-gated mem- expression. The subsequent transport of such proteins (or very pos-
brane cation channels that open following ATP binding [48]. They sibly transcripts) to peripheral and also central terminals permits a
thus have a role in transduction of chemical stimuli, which is in- more prolonged peripheral and centrally sensitised phenotype,
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 197

Fig. 3. Molecular basis of peripheral visceral nociceptive signalling before (1 and 2) and after (3–5) sensitisation. The main as yet proven steps in this process are
schematically demonstrated (see text for details).

respectively. Increases in peripheral expression of transducer in intrinsic neurons or small nerve endings (by limitation of avail-
channels are now well documented in human end-organ studies ability of human DRG or spinal cord tissues), experimental studies
in overtly inflammatory GI diseases [73,161,268] as well as in con- support these observations. Considering gastroesophageal reflux
ditions characterised by PS in the absence of inflammation disease as an example (a condition in which PS has been clearly
[3,30,59]. Although such changes have by necessity been observed demonstrated [127]), and increased TRPV1 correlated with
198 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

sensitivity [30,161], TRPV1 is upregulated in response to acid expo-

sure in DRG and nodose in a rat chronic reflux model [16] with
TRPV1 antagonists ameliorating ulceration in the model [270].
Numerous comparable studies exist for colonic inflammation
[68,173,261].

3.3. GI-specific sensitisation mechanisms

Of specific relevance to the gut is the additional presence of

intrinsic enteric sensory neurons as well as other specific cell types
such as enteroendocrine cells. It is eminently feasible that numer-
ous (approximately 100 million intrinsic versus 100,000 extrinsic)
afferents that are well known to express both SP and CGRP [93],
whilst not directly being able to transmit conscious pain, can nev- Fig. 4. Effects of distal oesophageal acidification on proximal oesophageal and chest
ertheless participate by releasing these neuropeptides in response wall pain thresholds to electrical stimulation. PT, pain threshold.

to noxious stimuli (via expressed transducer channels outlined

above) and thus promote neurogenic inflammation. It may thus
be that the above studies examining increases in intrinsic neuronal effects on adjacent spinal neurons leading to recruitment of previ-
expression of such molecules or indeed mucosal endings might be ously ‘silent nociceptors’ and hypersensitivity in areas (somatic
observing an indirect but important part of the process of GI sen- and visceral) that are remote from the site of peripheral sensitisat-
sitisation. In addition to the release of biogenic amines from mast ion (termed secondary hyperalgesia). In the GI tract, visceroso-
cells, enteroendocrine cells are also (unlike nearly all neurons) dis- matic convergence has been shown experimentally in a number
tributed in the epithelium itself and have the capacity to directly of gut regions and species, for instance, in the oesophagus of cats
‘taste’ the lumen. These cells are closely apposed to nerves supply- following sensitisation with acid [94]. The role of NMDA receptors
ing in the lamina propria and are able to basolaterally release sub- in this process, like that in somatic pain transmission, has been
stances such as 5HT – 98% of 5HT is in the GI tract [96], whose role confirmed experimentally [17,132].
in PS as well as in motor dysfunction is well established experi- Similarly, in humans, secondary hyperalgesia (by testing of the
mentally and in human conditions characterised by visceral hyper- relevant dermatome) has been demonstrated in a number of con-
sensitivity (VH) (see below). Very recent data suggest that mucosal ditions characterised by acute [228] and chronic abdominal pain
epithelial cells may also participate in PS in certain contexts such [40,174,241]. In addition, viscerovisceral: proximal oesophagus
as acid exposure with effects also in part mediated by TRPV1 [150]. and viscerosomatic: chest wall hyperalgesia has been demon-
strated in a well-validated human volunteer model of distal
3.4. Central sensory signalling and sensitisation oesophageal acidification (Fig. 4) [215]. This secondary hyperalge-
sia was both prevented and reversed with prostaglandin PGE2
The central terminals of nociceptors drive synaptic input to sec- [216] and N-methyl-D-aspartate (NMDA) receptor antagonists
ond-order neurons, transferring information about site, duration (ketamine) [258], suggesting that CS occurs by similar pathways
and intensity of the noxious stimulus. In the somatic nervous sys- to the somatic nervous system.
tem, it has been established that unlike low-threshold fibres that Balanced against these pro-nociceptive influences are the brak-
use glutamate as their sole transmitter, nociceptors use both this ing effects of endogenous opioids acting on mu and delta opioid
and a variety of neuropeptides, e.g. SP and 5HT, and trophic factors, receptors, GABA acting on GABAB receptors and endogenous cann-
e.g. BDNF, as transmitters and synaptic modulators [262]. There is ibinoids acting on CB1 ± 2 receptors. In the peripheral somatic NS,
reasonable evidence that GI nociceptors have a similar molecular these receptors are upregulated in response to central sensitisation
identity with experimental studies demonstrating that NK [138], [122]. Although this remains to be proven in the GI tract, there is
NMDA [132,192], AMPA [192] and 5HT [96] receptors present on sufficient experimental and clinical evidence to suggest that these
the post-synaptic membrane have a role in visceral pain transmis- receptors have similar roles in visceral pain modulation [200].
sion. In terms of pre-synaptic release of transmitters in response to
incoming action potentials, there is evolving evidence in the so- 3.6. Summary box
matic nervous system that voltage-gated calcium channels
(Cav2.2 and N-type) have a key role [262]. Such channels have
not to our knowledge been studied in GI afferents, although a sub- ! GI nociception is dependent on many of the peripheral and cen-
unit (alpha2delta) of Cav receptors is evolving as an area of thera- tral molecular mechanisms observed in somatic nociception.
peutic interest (below). ! Both peripheral sensitisation and central sensitisation have been
demonstrated as mechanisms in visceral pain.
3.5. Central sensitisation ! The roles of several ‘transducer’ cation channels, e.g. TRPs and
ASICs, are receiving particular attention because of their proven
Repetitive firing of action potentials from the periphery (as oc- activation by chemical agents that are in some cases specific to
curs with PS) leads to amplified responses to both noxious (hyper- the gut.
algesia) and innocuous (allodynia) stimuli [10]. Such facilitation is
triggered by greater pre-synaptic release of the above described
transmitters, which, acting at their respective receptors, lead 4. Modulatory influences on GI nociception
(much akin to PS) to increased intracellular calcium and calcium-
dependent activation of protein kinases A and C [123]. This in turn Whilst a body of work exists in somatic neuroscience to suggest
leads to phosphorylation of N-methyl-D-aspartate (NMDA) recep- that pain can be modulated by extra-nociceptive neuronal and
tors with a change in receptor kinetics that reduces their volt- non-neuronal influences, there is perhaps even greater evidence
age-dependent magnesium block, thus increasing subsequent that such factors can influence visceral sensation. This observation
responsiveness to glutamate [263]. Central sensitisation also has is rightly based on human stress experiences that evoke expres-
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 199

sions in common parlance such as ‘‘I had a gut feeling” or ‘‘I had the greater unpleasantness of visceral pain [230,231]. Recently,
butterflies in my stomach”. Such expressions are not unfounded, however, when unpleasantness was controlled for, some of these
with good evidence that both acute stress and state psychologic differences were less evident [82].
factors, such as affective co-morbidities, have important roles in An organism’s response to a stressor is generated by a network
chronic visceral as well as somatic pain conditions [12,107,251]. of integrative brain structures, in particular subregions of the
The link between negative emotion and unpleasant visceral sensa- hypothalamus (paraventricular nucleus, PVN), amygdala, and
tions has been well demonstrated experimentally in humans. For PAG. As already noted, these structures receive input from visceral
instance, anxiety, when induced by mental stress, has been shown and somatic afferents and from cortical structures, such as the
to increase the sensation of intestinal gas and increase pain during medial prefrontal cortex (PFC), and subregions of the ACC and insu-
sigmoid colon distension [87]. In addition to increasing pain per- la [14,217,243]. This network provides outputs to the pituitary and
ception, anxiety induction has also been shown to increase pontomedullary nuclei (such as the locus coeruleus, LC, and raphe
unpleasantness ratings to painful stimuli [250]. This latter effect nuclei), which in turn mediate the neuroendocrine and autonomic
may be related to increased activity in the brain areas discussed output to the body, respectively [14,217]. This central stress cir-
that are known to be associated with the affective-motivational cuitry is under feedback control via ascending monoaminergic pro-
component of pain processing. In the oesophagus, non-painful sen- jections from these brain stem nuclei, in particular serotonergic
sation is experienced as more unpleasant during a negative emo- (raphe nuclei) and noradrenergic (including LC) nuclei, and via cir-
tional context in comparison to a neutral emotional context, with culating glucocorticoids, which exert an inhibitory control via cen-
a positive correlation between intensity of the negative emotional tral glucocorticoid receptors located in the medial PFC and
context and the degree of insula and anterior cingulate cortex hippocampus. This complex network of brain structures modulates
activity observed using functional magnetic resonance imaging stress responses through an effector system referred to as the
(fMRI) [193]. Other studies have also shown anxiety induction to ‘emotional motor system’, the main output components of which
be associated with activity in the inferior frontal and temporal pole are descending spinal pathways, the ANS, and hypothalamo–pitu-
regions of the brain [125]. Given the importance of the vagus in itary axis (HPA) [167] (Fig. 5).
sensory feedback from the gut as well as its integration with the
limbic and paralimbic brain areas involved in homeostatic regula- 4.1. Descending spinal pathways
tion including pain modulation, it is not surprising that visceral
sensory experience is closely linked with emotional state. Func- Descending pathways from supraspinal centres can inhibit or
tional brain imaging studies have suggested differences between facilitate depending on the nature of visceral stimulus [209,218].
somatic and visceral pain in ‘‘limbic cortex” activation underlying At a cortical level, the ACC is the most important source of

Fig. 5. Highly schematic representation of effector pathways from higher cortical centres in response to external stressors. Following activation of cortical and subcortical
regions, such as the medial prefrontal cortex, subregions of the anterior cingulate cortex, insula and the hypothalamus release increased quantities of corticotropin-releasing
hormone (CRH) inducing the release of adrenocorticotropin (ACTH) from the anterior pituitary. This in turn stimulates the release of glucocorticoids from cells in the zona
fasciculata and reticularis of the adrenal glands. In response to ANS activation, cells of the adrenal medulla produce catecholamines such as adrenaline and noradrenaline, and
both effector arms have potential to modulate enteric neuronal and gut immunocyte activity.
200 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

descending modulation, projecting to the amygdala and periaqu- 4.3. Hypothalamic–pituitary–adrenal axis
eductal grey (PAG) of the mid-brain [10]. The PAG controls noci-
ceptive transmission by means of connections through neurons Animal studies have shown that responsiveness of these physi-
in the rostral ventromedial medulla and the dorsolateral pontine ologic systems and the ability to adapt can be altered by adverse
tegmentum. These two regions project through the spinal cord dor- early life events, and that this seems to increase the organism’s
solateral funiculus and selectively target the dorsal horn laminae susceptibility to the negative effects of stress in later life. Al-Chaer
that accommodate nociceptive relay neurons. This circuit can et al. demonstrated chronic visceral pain hypersensitivity in adult
therefore selectively modulate nociceptive transmission by its ana- rats that were subjected to either mechanical or chemical colonic
tomical proximity to primary afferent nociceptor terminals and irritation in neonatal life. Allodynia and hyperalgesia, the charac-
dorsal horn neurons that respond to noxious stimulation. Stimula- teristics of central neuronal sensitisation, were present in the ab-
tion of these sites inhibits responses of spinal neurons to noxious sence of any persisting peripheral pathology [7]. Early life events
stimuli. In the lower brainstem, the noradrenergic locus cereleus, can permanently influence the development of central corticotro-
serotenergic raphe nuclei and the rostrolateral ventral medulla re- pin-releasing hormone (CRH) systems, which, in turn, mediate
ceive inputs from the amygdala and PAG, and in turn project to the the expression of behavioural/emotional, autonomic, and endo-
dorsal horn of the spinal cord where incoming transmission can crine responses to stress. In rodent and non-human primate stud-
thence be ‘gated’ [10]. While much of this information has been ies, maternal deprivation in infancy is associated with enhanced
translated from somatic pain studies [199], a limited number of neural CRH gene expression and increased stress reactivity. In
studies in experimental animals [57,97,172,178,271] and some hu- adulthood, these animals show greater activation of the HPA axis,
man data [89] confirm that stimulating such areas can have anal- sympatho-adrenomedullary systems, and central monoaminergic
gesic effects by modulating visceral input. systems, and thus, greater vulnerability for stress-induced illness
[63,169]. Although these studies are not specific to the GI tract,
4.2. The autonomic nervous system (ANS) other animal studies have demonstrated that experimentally in-
duced stress in rats alters gut motility in a pattern similar to that
The ANS is a core part of the emotional motor system [113,165] seen in humans, and can be both mimicked by intracerebroventric-
and is a hierarchically controlled, bidirectional, body–brain inter- ular or intravenous administration of CRH and blocked by a CRH
face that integrates afferent bodily inputs and central motor out- antagonist, a-helical CRH [259]. Gue et al. reported that both stress
puts for homeostatic-emotional processes [119]. This is and the administration of CRH (either centrally or intraperitone-
particularly so for the viscera where, in addition to extrinsic nerves, ally) enhanced the number of abdominal cramps evoked by rectal
the ENS has been considered by some to be a further effector of the distension in a rat model without affecting rectal compliance, sug-
ANS [24,118]. Animal studies suggest that differences in visceral gesting a role of CRH in visceral hypersensitivity (see below). These
and somatic ANS pain response are largely mediated via defence effects were also antagonised by a-helical CRH [106]. This study
systems in which the roles of hypothalamus and PAG are best char- also demonstrated that peripheral administration of doxantrazole,
acterised. In particular, differential activation of either the ventro- a mast cell stabiliser, suppressed stress and CRH-induced rectal
lateral or lateral PAG, arising in response to pain from deep/ hyperalgesia to rectal distension [106]. It seems therefore that
visceral or superficial structures, respectively, results in variation mast cell mediators are involved in the hypersensitivity response
of patterned ANS defence responses and behaviours in animals to rectal distension induced by stress. Previous studies have also
(freeze versus fight-flight, respectively) [13]. Sympathetically med- highlighted the relationship between stress and colonic mast cell
iated mechanisms are implicated in several chronic pain syndromes degranulation, and the fact that these effects can be reproduced
[102,221], and animal and human data support a vagally mediated by the administration of CRH [52], however, the mechanisms by
inhibition of visceral nociceptive sensory inputs [75,198]. In this which CRH modulates mast cell function are still unknown.
way, the ANS has the potential to modulate visceral sensory percep-
tion. Iovino et al. determined the effect of increasing sympathetic 4.4. Summary box
(and reducing parasympathetic) activity on the perception of intes-
tinal stimulation. These autonomic modulations were induced
using lower body negative pressure which induces venous pooling ! Emotional state has important modulatory influences on GI
in the lower extremities [116]. Using brief distending stimuli in the pain.
intestine, the effect of lower body negative pressure on sympatheti- ! Several cortical and subcortical brain regions process central
cally mediated intestinal relaxation and on vagally mediated gastric responses to external stressors.
relaxation was measured by corresponding barostats. The effect of ! Visceral perception and pain can thence be influenced by three
lower body negative pressure on perception of duodenal distension main effector mechanisms: descending spinal pathways, the
was also compared to that on the perception of somatic stimulation. autonomic nervous system and the hypothalamo–pituitary axis.
It was found that lower body negative pressure significantly height-
ened perception of intestinal distension without modifying percep-
tion of somatic stimuli. Also, the reflex responses to duodenal
distension significantly increased both in the stomach and in the 5. Chronic unexplained gastrointestinal pain
intestine. These findings support the reported nociceptive and
anti-nociceptive actions of sympathetic and parasympathetic 5.1. Introduction
efferent systems, respectively.
The mechanism by which sympathetic and parasympathetic Abdominal pain is the commonest cause of presentation to a
nervous systems modulate pain is unknown. The pro-nociceptive surgeon or gastroenterologist [226], with abdominal or pelvic vis-
action of the sympathetic nervous system may relate to the release cera commonly implicated (by patient and/or physician), or proven
of catecholamines and/or prostaglandins from sympathetic nerve to be the site of origin. Acute abdominal pain may be caused by
terminals in close proximity to the terminals of damaged primary several mechanisms with clinical presentation commonly reflect-
afferent nerves. This in turn may result in the direct activation of ing the predominant underlying aetiology. Broadly, pain may arise
afferent fibres that have developed (or upregulated) a-adrenergic as a result of visceral stretching as occurs with obstruction, inflam-
receptors [118]. mation as occurs in inflammatory bowel disease, or invasion/com-
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 201

Table 2

(a) VH: experimental studies

! Provoked rodent pseudo-affective behaviours and visceromotor responses following neonatal (e.g. maternal separation) [7,21,22] or acute stress (e.g. restraint, water
deprivation, HPA activation) [1,41,52,106,139,259] and specific microbial-induced (e.g. Trichinella spirilis and Nippostronylus brasiliensis) [4,20,168] or chemical (non-
inflammatory e.g. dilute acetic acid) [55,266] luminal sensitisation, with
" Quantitative studies of immune cell activation, neuronal protein and gene expression following induction
" Modulation of these responses by pharmacologic blockade (selective antagonists) or gene knock-out

(b) VH: clinical studies

! Increased sensitivity to intraluminal stimuli (mechanical, electrical, chemical, and thermal) [38,170,203,215,253] and to stimuli of relevant somatic referral area (indic-
ative of CS) [40,174,195,215,241,255], and
" Effect of state or provoked psychologic effects on these responses [79,85,107]
" Modulation of these responses by pharmacologic therapy [see treatment section]

! Brain imaging studies (basal and with above stimuli) [166,170,202,242,256]

! Autonomic nervous system studies [2,247]
! Tissue studies on resected tissues or biopsies (mostly only mucosal biopsies) for immune activation [3,18,79,110] and nociceptor activation [3,54]

pression of nerves such as might occur in some cases of cancer. In a felt acutely or perceived as painful when stimuli exceed those in
sense, acute pain, e.g. trauma/surgery, or that with a treatable the physiological range. In this respect, colic occurs with supra-
cause, e.g. inflammation, is less problematic than chronic pain, par- physiologic visceral distension with stimulation of spinal mesen-
ticularly when this is not well explained. Highly relevant to the lat- teric (and possibly muscular) afferents, while ischaemic pain oc-
ter are two rather ill-defined and overlapping groups of conditions curs when blood flow in the mesentery falls below acceptable
in which chronic GI symptoms, commonly including pain, cause physiologic levels. Such stimuli that permit beneficial cognition
considerable chronic morbidity. These in current parlance are the of potential tissue damage are rarely chronic with the exception
functional gastrointestinal disorders (FGID) [80] and gastrointesti- of some cases of non-resolvable malignant obstruction or advanced
nal neuromuscular diseases [131]; terms that are at least partially mesenteric arterial disease, respectively. As noted earlier, however,
dependent on method of classification, with the former being pre- many patients without such organic illnesses do complain, some-
dominantly symptom-based and the latter measurement-based times bitterly, of chronic abdominal symptoms, especially pain.
using a combination of clinical, physiologic [260], and, when avail- Whilst it is possible that such pain could arise spontaneously in
able, histopathologic [130] criteria. Although the impact of visceral keeping with some somatic neuropathic conditions (below), there
pain in general should not be underestimated, these conditions is much more evidence to suggest that in certain circumstances it
perhaps represent the greatest challenge to healthcare in Western becomes possible to sense stimuli that are normally non-noxious
societies and are discussed in further detail. (analogous to allodynia) or increase afferent discharge to noxious
stimuli (analogous to hyperalgesia). These nociceptive hyperalge-
5.2. Functional gastrointestinal disorders: FGID sic phenomena, i.e. those occurring in response to a peripheral
stimulus, are usually grouped together under the title of visceral
5.2.1. Clinical overview and importance hypersensitivity (VH). VH is present only to a varying degree in
The term ‘irritable bowel syndrome’ is familiar now to most la- overtly inflammatory conditions [78,83,127], but is now firmly
ity, and is one of an array of over 40 adult and paediatric disorders established as the pathophysiologic ‘hallmark’ of FGID [104,171].
from mouth to anus classified (and reclassified) by a succession of In FGID, a plethora of studies have more than adequately dem-
committees from 1978 (Manning) onwards, with the latest being onstrated VH in most regions of the human GI tract (from oesoph-
Rome III [7]. These systems have correctly moved away from agus to rectum) [38,170,203,215,253]). For instance, in rectal
reductionistic models of disease that had previously often led to distension studies of IBS alone there have been at least 20 studies
inaccurate, demeaning and potentially harmful judgements being since that of Ritchie et al. [203], and numerous reviews
placed on patients without evident organic disease [80]. Using as [10,11,104,127,164].
a main basis the clustering of certain clinical observations with It is now generally held that there are four main co-operating
exclusion in some cases of an organic disease contribution, com- mechanisms of VH:
mon diagnoses using this system include several pain-predomi-
nant conditions such as irritable bowel syndrome (IBS), ! Sensitisation of afferent nerves (peripheral sensitisation).
functional dyspepsia, functional heartburn and functional abdom- ! Sensitisation of spinal dorsal horn neurons (central
inal pain syndrome. Pain is in fact the cardinal defining symptom sensitisation).
of IBS [149]. These variably morbid conditions are now responsible ! Altered descending excitatory or inhibitory influences (neural
for up to 40% of patients seen in secondary GI practice with consid- and humoral).
erable attendant health care costs. For instance, in 1998, a socio- ! Misinterpretation of non-noxious sensation as noxious due to
economic study demonstrated that the combined cost of health- cognitive and emotional biasing.
care utilisation and job absenteeism related to FGIDs was esti-
mated to be $41 billion per annum in the eight leading western It is clear that these mechanisms are at least in part encom-
economies [91]. Given the lack of strongly effective therapies for passed within the discussion above of molecular events in GI noci-
pain in FGID [50], there are clinically unmet needs in this area. ception and modulatory influences thereof. However, further
studies have attempted to address the contribution of these mech-
5.2.2. Applied pathophysiology: visceral hypersensitivity anisms more specifically to FGID and are summarised for brevity
It is evident that in normal conditions, the gastrointestinal tract (Table 2), with accompanying key references provided for the
is ‘conveniently’ not a source of conscious sensory experiences reader.
over and above registration of physiologic sensations such as full- Such interactions are best highlighted by considering the
ness and satiety. Thus, unpleasant sensations are generally only group (approximately 20%) of patients, who following a discrete
202 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

gastroenteritis episode have persistent symptoms including 5.3.2. Applied pathophysiology: neuropathic pain
abdominal pain – a condition now known as post-infectious IBS Although there is undoubtedly clinical overlap, the mechanisms
[177]. The pivotal role of PS in this process is supported by studies underlying pain in GINMD may significantly differ from those in
demonstrating increased numbers and activity of mucosal pro- FGID. In the established taxonomy of somatic pain research, VH
inflammatory cells, e.g. mast and enterochromaffin cells, as well must be regarded as a form of nociceptive hyperalgesia, i.e. requir-
as lymphocytes [18,79,110]. Although some contention exists ing peripheral stimulation. Despite the reporting of post-prandial
regarding their exact functional role, such cells have been docu- pain in some patients, there is surprisingly little physiologic evi-
mented to be closely apposed to nerves supplying the intestinal dence that VH is an important mechanism in GINMD. Indeed, most
mucosa, and to release a wide array of inflammatory mediators studies attest to a reduction in visceral sensation on direct stimu-
that can mediate PS [18,19,68]. Such changes can be replicated lation. For instance, although patients with slow-transit constipa-
experimentally in rodents with discrete peripheral (luminal) non- tion (chronic intractable and unexplained constipation) almost
inflammatory (infective or chemical) stimuli [4,18,20,55,266], universally complain of abdominal pain [129], several studies
and in humans can be demonstrated to lead to increased expres- demonstrate rectal hyposensation [98,129] rather than hypersen-
sion of molecules participating in peripheral nociceptor sensitisat- sitivity using the same stimulation paradigms used in IBS
ion, e.g. TRPV1 [3,59]. [170,253].
However, as already noted, cortical modulation is also impor- The nociceptor is designed to initiate activity only in response
tant. In a prospective study of 94 patients with gastroenteritis, to noxious stimuli at its peripheral terminal. Thus, action poten-
those developing post-infective IBS reported of more life events tials originating in the cell body or axon must be considered path-
and had higher hypochondriasis scores than non-IBS-developing ologically ectopic. In rodent nerve injury models of somatic pain,
patients [107], with this evidence contributing to more general ectopic activity occurs not only in response to changes in ion chan-
recognition that the potential to develop IBS can be influenced nel expression in injured fibres [66,146], but also because of the
by the presence of negative affective states and personality traits signals delivered to intact fibres from other cell types such as glia
[79]. Similarly, a very recent rectal distension study using fMRI and schwann cells that cause spontaneous firing [76,220]. The pos-
demonstrated that IBS patients with a history of abuse report of sibility that neuropathic mechanisms may contribute to the severe
more pain, greater MCC/PCC activation, and reduced activity of a pain seen in GINMD is supported by the following observations: (1)
region implicated in pain inhibition and arousal (sACC) [202]. Such the pain is often severe and unresponsive to standard analgesic
studies thus emphasise the importance of external stressors, cogni- therapies; (2) the pain is often not related to intraluminal stimula-
tive and emotional biasing as well as peripheral injury in GI pain. In tion, although it may be worsened in some; (3) there is good evi-
respect of descending modulatory pathways, studies of CRH recep- dence for enteric neuropathy (degeneration and/or loss of
tor antagonists in FGID patients (below) further affirm the strong neurons) in these disorders [83,130,133,239,249], as well as for
modulatory role of the HPA axis in gut sensorimotor function the two other histopathologic components of the three described
and the possibility that derangements of its normal function occur in neuropathic pain [220] – reactive gliosis [83,249] and perineural
in patients with FGID. Similarly, autonomic alterations such as low immune cells [130,239]; and (4) the pain cannot simply be the
basal cardiac vagal tone have special relevance to pain sensitivity result of distension since most, particularly adult, patients do not
and have been observed in patients with IBS [2,247]. have radiologic evidence of distension [130]; indeed those with
constant intraluminal dilatation and significant abdominal
5.3. Gastrointestinal neuromuscular disease (GINMD) distension as a result of myopthy do not always complain of pain
(the main problem being one of vomiting and malnutrition) [158].
5.3.1. Clinical overview and importance Surprisingly, despite the vast body of work examining neuro-
It is well acknowledged even by steadfast Rome protagonists pathic pain mechanisms in somatic research [66,262], and some
that a subgroup of patients with severe unexplained abdominal suggestion that it has a role in chronic pancreatitis [74], this
symptoms have demonstrable underlying abnormalities affecting hypothesis has to our knowledge not been considered in GI pain
the functional syncytium of differing cell types (intrinsic and studies. A paucity of studies have, however, examined the effects
extrinsic nerves, smooth muscle, interstitial cells of Cajal (pace- of pelvic denervation in animal models as a surrogate for physio-
makers of gut motility and regulators of neuronal input to smooth logic disturbances in humans following hysterectomy and child-
muscle cells)) responsible for normal GI sensorimotor function. birth [53]. Pelvic denervation in rats causes not only reduced
These disorders may be due to relatively rare congenital defects, thresholds to colonic distension but also some spontaneous activ-
for example, Hirschsprung disease, where the pathophysiologies ity [64,232]. In humans, extrinsic denervation, suggested to occur
are to some extent elucidated [109], however, most GINMDs are after hysterectomy, leads to physiologic evidence of desensitisa-
acquired in later life where their aetiology may be unknown (pri- tion [128,129], yet such patients frequently complain of abdominal
mary or idiopathic) or associated with another established disease and pelvic pain [29]. Although this argument potentially neglects
(secondary), e.g. paraneoplasia, connective tissue disorders. Com- confounders such as false attribution, altered pelvic anatomy, de-
mon to most GINMD are symptoms of impaired motor activity feminisation, and the effect of constipation (a frequent accompani-
which manifest as slowed or obstructed transit [260] with or with- ment) [29,128], the possibility that spontaneous firing of afferents
out evidence of transient or persistent radiologic visceral dilatation at a peripheral or central level might contribute to pain in GINMD
[158,227]; thus diagnosis (and classification), in the absence of his- as in somatic pain is an under-explored area.
tologic proof of neuropathy, myopathy or mesenchymopathy, is
usually made using specialist GI physiologic measurements 5.4. Summary box
[260]. Primary diagnoses on this basis include enteric dysmotility,
intestinal pseudo-obstruction and slow-transit constipation, all of
which are characterised by abdominal pain [130,227,239]. Whilst ! Unexplained abdominal pain represents a significant healthcare
perhaps the ‘‘tip of the iceberg” of unexplained gut dysfunction, burden.
these conditions result in considerable individual morbidity and ! Visceral hypersensitivity is regarded as the pathognomonic fea-
incident mortality from a variety of sequelae including intestinal ture of functional gastrointestinal disease (FGID) and has several
failure and suicide, sometimes as a result of unmanageable abdom- well-established peripherally and centrally co-operating
inal pain [130,227]. mechanisms.
 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209 203

! Neuropathic pain is a possible, yet underexplored mechanism, formed. Nevertheless, ‘evolving’ compounds are discussed below
particularly in GI neuromuscular disease (GINMD). using the broad divisions used previously in the review. In GINMD,
there are almost no well-designed clinical trials.

6.3. Drugs acting predominantly on peripheral signalling and

6. Treatment of chronic gastrointestinal pain sensitisation

6.1. Anatomically-based treatments Many potential targets have been discussed with relevance to
modulating the complex set of molecular events underlying
The anatomical basis for GI pain has been discussed. One ap- peripheral nociceptive transmission and in particular PS. Com-
proach to treating intractable pain of GI origin might thus be inter- pounds have been developed that target some of all the three
ruption of these pathways. Nerve blocks are well established in groups of receptors involved in these processes: voltage-gated
somatic, particularly radicular, pain from the spine. In chronic GI ion channels, ligand-gated cation channels and GPCRs, as well as
pain, their role has largely been limited to one of the adjuvant ther- those affecting the bidirectional interaction of these molecules
apies (in addition to opioid analgesics) in palliation from inopera- with local pro-inflammatory and immune cells. The following
ble advanced retroperitoneal (usually pancreatic) or pelvic descriptions are limited to drugs acting on neurons rather than
malignancy [201]. Such pain may arise as a result of (1) direct tu- modulating other immune interactions, e.g. probiotics.
mour involvement of nerves, e.g. pelvic/sacral afferents, or of the
viscus itself leading to obstruction or ischaemia, or (2) be associ- 6.3.1. Voltage-gated ion channel blockers
ated with treatment, e.g. radiation neuritis, drug-induced neurop- Such molecules have the potential to address the fundamentals
athy/constipation, or surgical denervation (discussed above). of pain transduction. Allowing for toxicity and non-specificity,
Invasive therapies are in general reserved for patients in whom some anticonvulsant drugs, e.g. carbamazepine and lamotrigine,
pharmacologic and other non-invasive therapies are ineffective have been trialled in somatic neuropathic pain with limited efficacy
[117], and include a variety of nerve blocks that may be diagnostic (Cochrane review: [254]). Although still agents of interest in neuro-
(to determine origin of pain), temporarily therapeutic or as a guide pathic and inflammatory pain [262], in the GI tract to our knowl-
to permanent intervention and its side effects, e.g. neurolytic edge only topical rectal lidocaine has been used in patients with
blocks/surgical division [201]. Very recent advances such as endo- IBS-related pain [240], with a further more detailed trial completed
scopic ultrasound-guided celiac axis block are also being made but unpublished (Clin Trials ID: NCT00108446), and carbamazepine
[144]. On this basis, approximately 50–80% of pelvic cancer pain has been used in the rare familial rectal pain syndrome [208]. More
patients benefit from nerve blocks [191,205] usually using (after selective sodium channel agents have yet to be developed. Mecha-
previous test injection) intrathecal injection of phenol or alcohol nosensitive potassium channels have not been addressed as phar-
to destroy nerve roots. Sympathetic blockade from the pelvis re- macologic targets but are a subject of current interest.
quires interruption of spinal afferents following the sympathetic
innervation, usually by CT-guided needle neurolytic infiltration of 6.3.2. Cation channel blockers
the superior hypogastric plexus [194]. Sacral surgical rhizotomy, The potential to modify the responses of a variety of such chan-
although sometimes effective [214], has largely been abandoned nels has been explored in somatic pain, and less so in visceral pain.
for benign and malignant deep pelvic/perineal pain not least Compounds directed to TRP, ASIC and P2X channels although ex-
because of profound subsequent bladder and bowel dysfunction plored in preclinical settings have had only modest progress to
[128]. More pertinent to current practice is, however, the rapidly clinical trials [234] with the only study registered for GI pain
developing area of sacral nerve stimulation (SNS). SNS is fast now terminated (GSK: NCT00461682: rectal pain in IBS). In gen-
becoming the first-line invasive therapy for faecal incontinence eral, such drugs must therefore be considered to be at an early
and constipation [99,156]. In respect of the latter, it has been noted stage of development. In respect of serotonin, several studies have
that unlike other surgical treatments in which pain is usually unaf- examined the effect of 5HT3 antagonists as therapeutic agents in
fected (even when defaecation is improved), SNS has beneficial ef- IBS. Drugs such as alosetron, cilansetron and ondansetron were
fects for pain in patients with severe constipation [99,158] and developed focusing mainly on their inhibition of motor activity
may emerge as a therapy for pelvic pain. [49,71]), however, their effects on VH have also been studied
where there is conflicting evidence regarding a true, as opposed
6.2. Pharmacologic modulation of GI pain to secondary (due to increased compliance), peripheral visceroan-
algesic effect [46,70, reviewed: 162].
As for VH, there are several reviews of new and evolving phar-
macologic therapies for FGID and particularly IBS [50,112,163]. 6.3.3. G-protein coupled receptors
Current management of pain in FGID involves the use of analgesics, Perhaps more so than the above groups of receptors, this class of
antispasmodics or antidepressants which often produce counter- receptor holds most promise in novel peripheral treatments of GI
productive side effects such as constipation or nausea. Pharmaceu- pain. Broadly speaking, drugs have been developed to modify the
tical companies have invested heavily in the last two decades to bidirectional interaction between pro-inflammatory molecules
develop the ‘magic bullet’ for managing pain in FGID. However, and their receptors on neurons, with some modifying release and
their efforts have not met with success with nearly all now having others blocking effects. Current trials based on the experimental
withdrawn from financial investment in this area. Most drugs evidence presented above include drugs acting at further serotoner-
developed on the basis of promising preclinical studies have shown gic targets, especially the 5HT4 receptor. As with 5HT3, this receptor
either no effect or only a modest effect in clinical trials [50]. Part of has predominantly been explored as a target for modulation of mo-
the problem is that FGIDs are diagnosed on the basis of symptom- tor function to increase transit in constipation using agonists, e.g.
based criteria and with considerable inter-individual differences in Tegaserod [121]. Whether such drugs can affect visceral sensitivity
pathophysiology leading to heterogeneity in study populations and is controversial [46] with some animal [103] but limited human
endpoints [163]. Furthermore, there is a lack of disease biomarkers data [62]. Proteinase-activated receptor 2 (PAR2) antagonists have
and good models of disease that can be used to test the proof of the potential to modulate visceral pain by acting on a variety of
mechanism for the drugs before large-scale clinical trials are per- cells including sensory afferent terminals, as well as by altering
204 C.H. Knowles, Q. Aziz / PAIN 141 (2009) 191–209

paracellular permeability to mucosal inflammatory cells [1]. Other from grace. Very recent data suggest that some parasympathetic
agents such as those acting at neurokinin [213], CCK [39] and pros- agonists may also be effective [120]. Finally, antidepressants such
taglandin receptors [216], despite having biologic rationale at as SSRIs have been demonstrated to reduce visceral sensitivity in
peripheral as well as central levels, have failed to demonstrate suf- two studies of IBS [134,196].
ficient efficacy [81,257]. Others such as bradykinin and histamine
receptors have yet to be studied in human GI pain conditions.
7. Conclusions

6.4. Drugs acting predominantly on central signalling and sensitisation

The GI tract is an important site of pain which may unfortu-
nately be chronic and unexplained. The field of GI pain research
Although not exclusively active centrally, a number of drugs
is starting to produce results that although temporarily still behind
have been developed that act either to block excitatory transmis-
those in somatic pain are nevertheless becoming subject to the
sion or promote inhibition. In respect of the former, robust analge-
same scientific rigour. Increased understanding of the detailed
sic responses have been shown in response to u and kappa opiate
pathophysiology of important GI pain syndromes is permitting
analgesics in animal models [137], in healthy humans suffering
the development of novel drugs that may have more established
gastric distension [61], and in patients with IBS using rectal sensi-
clinical roles in the future.
tivity as a surrogate marker [69,70]. However, further development
of drugs such as fetotozine in this context seems to be lacking with
none currently listed on clinical trials.gov. Nevertheless, other re- Conflict of interest
cent studies demonstrate the efficacy of using specific partial opi-
oid agonists/antagonists to counteract analgesic-related None declared.
constipation [238,248]. Similarly, blockade of NMDA receptors
has been shown to have clear analgesic benefits in GI pain in ani- Acknowledgements
mal models [17,132] and as noted blocks CS in a model of human
oesophageal sensitivity [258]. However, drugs such as ketamine Dr. Peter Paine and Dr. Abhishek Sharma who were both PhD
are unlikely to gain widespread acceptance given their global students of Professor Aziz are acknowledged for contributions to
anaesthetic effects. the text in the sections on GI pain modulation: beyond the
Alpha2delta ligands such as gabapentin and its more potent nociceptor.
successor pregabalin have proven efficacy in neuropathic pain by
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