Gu, 2001;48:125-13 1
`
`125
`
`Occasional viewpoint
`
`Visceral hypersensitivity: facts., speculations., and challenges
`
`Visceral hypersensitivity is currently the holy grail ... .it is
`widely regarded as the reason for the development of func(cid:173)
`tional gastrointestinal diseases, including functional dys(cid:173)
`pepsia and irritable bowel syndrome.' Although the field
`has advanced considerably in the past decade, it is
`necessary to take stock and realistically appraise our
`current understanding. Identifying issues of controversy
`will help address the directions or priorities to advance this
`field in the future. Thus our objectives are to review the
`current understanding of the neuroanatomy and physiol(cid:173)
`ogy of gut sensation, briefly review examples of the
`relationship between symptoms and sensorimotor dysfunc(cid:173)
`tion, and discuss controversies and speculations requiring
`more thorough study. In pursuing this discussion, we have
`drawn on experience and data from several regions of the
`gut as work in a single region does not provide the compre(cid:173)
`hensive or broad perspectives necessary.
`
`Neuroanatomy and physiology of sensation
`Enteroendocrine cells in the lining of the gut serve as
`chemical and mechanical transducers for local reflexes (for
`example, peristalsis) or initiation of afferent projections to
`the central nervous system.' 2 As with somatic sensation,
`gut afferent signals reach conscious perception through a
`three neurone chain.2 The first order neurone, whose cell
`body is in the dorsal root ganglion, terminates in the dorsal
`column laminae of the spinal cord (fig 1). Enpassantfibres
`project to noradrenergic neurones in prevertebral ganglia,
`and this reflex centre results in modulation of viscus func(cid:173)
`tions, including motility. Somatic and visceral afferents
`converge on dorsal horn neurones and result in viscero(cid:173)
`somatic projection or referred pain. Descending modula(cid:173)
`tory fibres (serotonergic, adrenergic, and possibly others)
`from brain stem centres such as the periaqueductal grey
`alter the sensitivity of the dorsal horn neurones and thus
`serve to centrally control the intensity of perception during
`visceral stimulation (fig I).'
`The second order neurone projects from the dorsal horn
`of the spinal cord to the thalamus and reticular formation in
`the brain stem (fig 1). The ascending pathways are located
`in the spinoreticular and spinothalamic tracts. Recently, a
`nociceptive spinal pathway was identified in the dorsal col(cid:173)
`umn in primates; these project nociception from viscera
`such as the colorectum, pancreas, and duodenum.' •
`These second neurones synapse with autonomic and
`satiety centres and with the third order neurone that leads
`to emotional responses (limbic system) and conscious per(cid:173)
`ception (sensory cortex). These projections lead to changes
`in pulse rate, blood pressure, appetite, and emotions in
`response to visceral pain. The loci of projection in the sen(cid:173)
`sory cortex are still not fully understood; there is evidence
`that the anterior cingulate cortex, insula, and cerebellum
`are activated during distensions of the oesophagus,
`stomach, and rectum.
`Currently, we have a limited understanding of the cerebral
`processing of visceral stimuli, the pathways and mediators of
`visceral afferents, the role of end organ modulation of sensa(cid:173)
`tion, and association of symptoms with some sensorimotor
`dysfunctions. These will be reviewed below but it is essential
`to acknowledge the many gaps in our understanding. These
`gaps are particularly evident in comparison with the
`
`Brain
`
`Sensation
`
`Ascending
`spinothalamic
`and spinoreticular
`fibres
`
`. .
`
`GI tract
`
`Desending adrenergic and
`serotonergic fibres
`Figure 1 Three order ,ieurone chain resulting in visceml perception; ,zore
`the ,lesce,u/i,zg path~s converging on the dorsal ham ,ieurone modulating
`the proj,cr:io,,., from thts relay station to the surfaa atul to the bra111.
`
`thorough characterisation of transmitters/mediators'... in(cid:173)
`volved in the reflex responses at the prevertebral ganglia. The
`candidate transmitters in visceral perception include sero(cid:173)
`tonin (5-HT), calcitonin gene related peptide, substance P,
`norepinephrine, and opiates (peripherally at kappa recep(cid:173)
`tors, centrally at mu receptors).'• '0 There are receptor sub(cid:173)
`types for all of these transmitters and advances in therapy
`will require full characterisation of the roles of transmitters
`and receptors along the sensory neural axis.
`
`Definitions of visceral sensation parameters
`Prior to discussing the pros and cons of measurements and
`the relationship between physiological parameters and
`symptoms, a few definitions are essential.
`(1) Accommodation is relaxation of the stomach in the early
`postprandial period. Using the barostat, wall tone has
`been assessed by the relative change (that is, not an
`absolute measurement) of stomach volume under
`constant pressure. However, the volume of accommoda(cid:173)
`tion can also be measured with novel imaging methods
`(for example, magnetic resonance imaging or single
`photon emission computed tomography, discussed
`below).
`
`Abbreviations used in this paper : ms, irritable bowel syndrome.
`
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`

`126
`
`Camilleri, Coulie, Tack
`
`(2) Compliance is the volume response (y axis) to an
`imposed pressure (x axis) and it has a sigmoid
`relationship with initial reflex relaxation (change in
`wall tension without volume change), followed by a
`linear section that reflects partly the elasticity of the
`viscus wall, and a final plateau phase (fig 2).
`Compliance is inversely related to elastance. Wall
`compliance is measured by means of isobaric stepwise
`(ramp) distension (for example, with a barostat). The
`nature of the balloon (latex v polyethylene) and the
`method of inflation influence the results.11–13
`(3) Wall
`tension has been calculated using the law of
`Laplace (T»P.r), derived with a slight di Verence in the
`formula for the actual shape (for example, cylinder,
`sphere) of the balloon in the viscus segment tested. This
`measurement assumes
`several
`factors which are
`unknown in most human experiments (discussed
`below under “Stretch versus tension modulation of
`aVerent discharges”). It was claimed that measure-
`ment of tension would be more relevant to understand
`sensory changes14 but correlation of sensation in
`response to tension based stimuli may not be
`significantly better than with pressure based stimuli.
`(4) Hypersensitivity, hyperalgesia, allodynia. Hypersensitivity
`refers to increased sensation of stimuli. In practice, this
`is appraised by measurement of threshold volumes or
`pressures for first sensation or pain. Alternatively, it
`refers to the increased scores of symptoms (including
`pain) in response to standard stimuli. Hyperalgesia
`refers to increased pain sensation in response to a cer-
`tain stimulus. Allodynia refers to the appreciation that
`a stimulus, which was previously not perceived as
`being painful, becomes painful. These terms, which
`were originally used in reference to somatic sensation,
`have been adapted to studies of visceral sensation.
`
`Stretch versus tension modulation of aVerent
`discharges
`Although the reasons for hypersensitivity to distension are
`unclear, mechanoreceptors must be activated to initiate,
`convey, or perceive the distending stimulus. It has been
`proposed that mechanoreceptors are either in series or in
`parallel with muscle fibres.
`In animals,
`in parallel
`mechanoreceptors respond to stimuli that elongate the
`stomach wall;
`in series mechanoreceptors respond to
`stimuli
`that
`increase the tension within the stomach
`wall.15 16 Figure 3 illustrates the responses of tension mech-
`anoreceptors (in series) and elongation mechanoreceptors
`(in parallel) to diVerent stimuli (distension, relaxation, and
`contraction of smooth muscle). In series receptors are acti-
`vated during distension and contraction against a resist-
`ance; conversely, in series receptors are inactivated during
`
`250
`
`200
`
`150
`
`100
`
`50
`
`Volume (ml)
`
`0
`
`0
`
`10
`Pressure (mm Hg)
`Figure 2 Example of a compliance curve (volume response to imposed
`pressure) in a segment of human colon. The curve is obtained by stepwise
`increments of intraballoon pressure and simultaneous measurement of
`intraballoon pressure. Note the initial “cushion” in which an increase in
`pressure does not result in any change in volume. The second portion of the
`compliance curve is more linear and partly reflects the elasticity of the viscus.
`
`20
`
`In series
`
`In parallel
`
`Activated
`
`Activated
`
`Inactivated
`
`Activated
`
`Distension
`
`Relaxation
`
`Contraction
`
`Activated
`Inactivated
`Figure 3 Schematic illustration of responses of tension mechanoreceptors
`(in series) and elongation mechanoreceptors (in parallel) to distension,
`relaxation, and contraction of gastric smooth muscle. Mechanoreceptors are
`modelled as coils and positioned in parallel (right) or in series (left) to the
`muscle. In series, receptors are activated during distension and contraction
`against a resistance; they become inactivated during relaxation. In parallel,
`receptors are activated during distension and relaxation, and become
`inactivated during contraction.
`
`receptors are activated during
`relaxation. In parallel
`distension and relaxation and are inactivated during
`contraction.
`In human studies, gastric distension results in elongation
`as well as increased wall tension of the stomach; the stom-
`ach also reflexly responds to the stimulus applied by
`contracting. Hence it is unclear which of these two types of
`mechanoreceptors mediates sensitivity to distension of the
`proximal stomach in vivo. Observations made in recent
`studies provide arguments for involvement of both types of
`receptors. For example, during postprandial gastric
`accommodation, an increase in proximal gastric volume
`(and hence elongation) occurs but this does not cause
`food
`enhanced perception17 18 until a large volume of
`stimulates a sense of satiety and fullness. The latter is
`probably mediated by a change in wall tension from the
`pressures imposed by food and reflex contractions. In
`humans, one way to assess the roles of volume versus ten-
`sion in gastric sensation is to evaluate the eVects of high
`volume clamping by fixed volume inflation of a balloon
`while pressure is allowed to vary. This allows measurement
`of muscle tension while changes in muscle length are
`“neutralised” by the high volume clamp. In this experimen-
`tal setting, phasic contractions which are associated with
`phasic increases in wall tension cause enhanced percep-
`tion, probably through in series receptors which are under
`increased “load” with viscus contraction.19
`Thumshirn and colleagues20 demonstrated that wall ten-
`sion, estimated by Laplace’s law, was significantly corre-
`lated with sensation scores (r=0.4, p<0.05) during a phar-
`macological study of gastric sensitivity, suggesting that
`>80% of the sensation variance (1−r2) is attributable to
`other factors, such as visceral aVerent functions or central
`control (spinal or supratentorial). To assess the relative
`contribution of both receptor types in mediating sensation
`in vivo, novel approaches and more sensitive methodology
`are needed. Distrutti and colleagues14 suggested that a
`“tensostat” may facilitate this task but the relationships (r
`values) between symptoms and tension or pressure in their
`work diVered minimally. An alternative method, which has
`been used to measure rectal wall tension, is impedance
`planimetry; increased wall tension was associated with
`greater sensation of the need to defecate. However, similar
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`Visceral hypersensitivity
`
`127
`
`increases in sensation were observed with increases in dis-
`tension pressure.21
`It has been suggested that the simplified law of Laplace
`can be used to estimate wall tension during barostat stud-
`ies of hollow organs, and that this level of wall tension
`determines the level of perception during distension stud-
`ies.14 However, this formula makes a number of assump-
`tions that are not necessarily fulfilled by the extant experi-
`mental conditions. Those assumptions include: the wall of
`the viscus is infinitely thin; the intraluminal balloon and
`viscus have a perfectly defined (for example, spherical)
`shape that can be defined mathematically; the pressure
`external to the viscus is known and is evenly distributed.
`Most importantly, the Laplace formulae do not take into
`account the modulatory eVects of changes in the contrac-
`tile state of the viscus which may occur reflexly or in
`response to neurohumoral or pharmacological modulation
`and which are superimposed on the compliance of the hol-
`low organ. The limitations in current assessments of
`tension with tensostat or barostat were recently discussed
`by Gregersen22 who emphasised the error in the assump-
`tion that tension is equal throughout the proximal stomach
`(that is, isotropic), particularly in view of the complex and
`variable geometry of the stomach within and between indi-
`viduals. These diVerences in geometry render invalid a
`theoretical attribution of shape (for example, spherical v
`ellipsoid v more complex).
`A strict application of Laplace’s law to isobaric measure-
`ments also appears to lead to conclusions that conflict with
`daily experiences. For example, relaxation (or elongation of
`the circumference) of the proximal stomach under isobaric
`conditions would predict increased wall tension as T~r
`when P is constant. Thus if tension was the determining
`factor in sensation, Laplace’s law would predict increased
`sensation at times when the viscus is relaxed, for example
`during the 3–5-fold increase in gastric volume that occurs
`within five minutes of starting a meal. Conversely, under
`conditions of adequate accommodation and of pharmaco-
`logical relaxation, the experimental evidence suggests that
`symptoms elicited by mechanical stimuli are usually
`reduced in healthy subjects,17 20 unless massive relaxation is
`induced.
`
`Measurement of visceral sensations
`In general, the literature in humans shows two types of vis-
`ceral sensation measurements in vivo (fig 4). The first
`addresses the sensation of mechanical, electrical, or other
`stimuli applied within the gut, and uses standardised
`symptom based questionnaires (visual analogue scale or
`adjectival scale) to determine thresholds or severity of
`symptoms induced. The second method measures changes
`in cerebral blood flow using positron emission tomography,
`
`Visceral sensation: methods for measurement
`
`Function
`
`Method
`
`Sensation of mechanical stimuli
`
`Threshold
`
`AML, tracking,
`random staircase
`
`VAS
`
`Phasic distensions
`
`Cerebral blood flow
`
`PET, fMRI, SPECT
`
`Figure 4 Schema demonstrating distension paradigms used in visceral
`sensation studies. PET, positron emission tomography; fMRI, functional
`magnetic resonance imaging; SPECT, single photon emission computed
`tomography; VAS, visual analogue scale; AML, ascending method of
`limits.
`
`functional magnetic resonance imaging, or single photon
`emission computed tomography during visceral stimula-
`tion.
`
`METHODS OF MEASURING SENSORY THRESHOLDS
`Methods of measuring the threshold for initial perception
`or discomfort/pain have generally used ascending method
`of limits, tracking, or a random staircase design.12–14 In
`these methods, sequentially increased pressure or volume
`distensions are delivered until the subject perceives either
`first sensation or the symptom of discomfort/pain. After the
`threshold is identified, a computer method randomly
`delivers a pressure or volume stimulus which is either
`above or below the previously identified threshold. This
`serves to fine tune the level of the threshold for either vol-
`ume or pressure distensions. In the random staircase
`method,
`the stimulus paradigm does not necessarily
`increase continually as in ascending method of limits but
`randomly applies the stimulus either of greater or lower
`intensity to try to avoid response bias.23 While these meth-
`ods have received a great deal of application in the
`literature, their sensitivity and potential for response bias
`have not been adequately assessed. For example, when
`ascending method of limits and tracking are used to assess
`first perception and pain, it is possible that the subject will
`be interrogated 40 or 50 times while assessing the thresh-
`olds. This clearly could introduce an element of response
`bias which is probably worse with increasing number of
`distensions.
`
`DISTENSIONS USING PRESSURE BASED MECHANICAL STIMULI
`To avoid the potential inaccuracies introduced by response
`bias, we have used a restricted number (three to five) of
`distensions using pressure based mechanical stimuli which
`are applied in a randomised order.20 24–26 During disten-
`sions, the individual is asked to complete a visual analogue
`scale pertaining to the symptoms that are of interest (for
`example, pain and gas in the colon; pain and urgency in the
`rectum; or bloating, nausea, and pain in the stomach).
`
`CEREBRAL BLOOD FLOW MEASUREMENTS
`Cerebral blood flow measurements are intended to identify
`the projections in the brain of visceral stimuli applied in the
`gut. These will be discussed in greater depth below. How-
`ever, it is important to realise that changes in cerebral
`blood flow detected by these methods range from 2% to
`5%. Sensitivity to detect increases in cerebral blood flow
`over background activity, with variations unrelated to the
`specific stimulus, is somewhat vulnerable because of the
`relatively low absolute changes in blood flow that can be
`expected.27–29 Thus there is a low signal to noise ratio which
`renders interpretation diYcult.
`
`Symptoms and disturbed sensorimotor functions:
`any role as a biological marker?
`Irritable bowel syndrome (IBS) is associated with rectosig-
`moid hypersensitivity30 31 which has been postulated to
`represent a biological marker for IBS.32 Several lines of evi-
`dence lead us to question this suggestion. Firstly, across
`studies, the prevalence of rectal hypersensitivity in IBS is
`20–80% and may only be demonstrable in response to
`repetitive stimuli rather than single stimuli. Secondly, there
`was only a weak correlation between rectal sensory thresh-
`olds and current pain, and no significant correlation with
`pain severity in the prior two weeks.33 Thirdly, changes in
`rectal sensory thresholds did not predict response to
`therapy in one study reported to date.34 Fourthly, demon-
`stration of rectal hypersensitivity has not yet contributed to
`the diagnosis or alteration of pharmacotherapy in IBS.
`Fifthly,
`the increased sensation has been shown to
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`128
`
`Camilleri, Coulie, Tack
`
`coincide, in some studies, with the timing of reflex rectal
`contractions, suggesting that there is also a motor compo-
`nent to the augmented sensitivity.31 Hence it should to be
`emphasised that application of rectal sensation tests in the
`diagnosis or management of IBS is premature. The meth-
`odology for sensory testing is not yet standardised (for
`example, ascending method of limits, tracking, random
`staircase) or completely validated (for example, coeYcient
`of variation, test-retest reliability, sensitivity, specificity).
`Several studies have confirmed that, as a group, patients
`with functional dyspepsia are hypersensitive to isobaric and
`isovolumetric balloon distension of the proximal stom-
`ach,17 35 that is, the thresholds for first perception and dis-
`comfort are lower
`in dyspeptics
`than in controls.
`Hypersensitivity to gastric distension is a feature of
`functional and not organic dyspepsia.36 It is not known if
`gastric sensory thresholds are correlated with current or
`recent symptom severity or if hypersensitivity is associated
`with specific symptoms in functional dyspepsia patients. A
`preliminary study reported that almost half of functional
`dyspepsia patients have hypersensitivity to gastric disten-
`sion, and that postprandial pain is significantly more
`prevalent in these patients.37 However, one can question
`the relevance of fasting perception thresholds as a biologi-
`cal marker for functional dyspepsia, which is by definition
`a symptom complex that occurs in the postprandial period.
`Patients who report pain during fasting gastric distensions
`are potentially more prone to report postprandial pain;
`pressure induced increased sensation during the postpran-
`dial period may be a better marker of
`functional
`dyspepsia.38 39
`Several authors have shown that functional or non-ulcer
`dyspepsia patients have reduced postcibal gastric accom-
`modation compared with controls.18 38 Among 40 consecu-
`tive non-ulcer dyspeptics who underwent measurement of
`gastric accommodation, Tack and colleagues18 demon-
`strated that early satiety and weight loss were significantly
`more frequent in patients with impaired versus normal
`accommodation. As fasting gastric compliance is normal,
`these data suggest heightened sensitivity of the sensory
`apparatus from gut to cortex, with presumed modulation
`of hypothalamic or other satiety centres.
`
`Controversial interpretation of visceral sensation
`data
`In the next section we will address a number of controver-
`sial issues pertaining to visceral sensation. Such controver-
`sial statements and interpretations include the following:
`(1) If a drug alters perception without a change in compli-
`ance, the drug must aVect visceral aVerent function.
`(2) Wall tension determines the level of sensation in a vis-
`cus.
`(3) Relaxation results in reduced perception.
`
`COMPLIANCE AND PERCEPTION
`The interpretation of perception data in response to phar-
`macological perturbations has incorporated measurements
`of organ compliance. Thus when compliance is unchanged
`but sensation is, it has been implied that aVerent nerve
`function has been altered. This is illustrated by the exam-
`ple of octreotide, which alters sensation without changing
`compliance,40–43 suggesting that its eVect must be on aVer-
`ent nerve function. However, octreotide also reduces post-
`prandial colonic tone, suggesting that it may blunt reflex
`contraction to physiological
`stimuli44; another
`study
`suggested octreotide did not alter either rectal sensation or
`compliance.45
`Compliance data are far more complex than would be
`suggested from the linear interpretation of data that have
`typically been applied to the compliance curves. Thus in
`
`the gut, compliance curves have an initial “cushion” in
`which an increase in pressure does not result in any change
`in volume (see fig 2). This accommodation to a pressure
`stimulus can be altered by a pharmacological perturbation,
`such as with an ♡
`2 adrenergic agonist. This portion of the
`compliance curve can be assessed mathematically by
`estimating the ♢ component on a power exponential analy-
`sis of the compliance curve26 or the inflection point in the
`curve.32 The physiological contribution of tone and tension
`to this part of the compliance curve has not been fully
`evaluated.
`The second portion of the compliance curve is more lin-
`ear and partly reflects the elasticity of the viscus. This may
`explain why compliance is rarely altered by diseases, except
`those associated with replacement fibrosis (scleroderma,
`radiation) or by drugs. Clonidine significantly alters the
`linear portion of the colonic compliance curve,26 suggesting
`that neuromuscular function may partly alter this aspect of
`compliance.
`
`TENSION
`The relationship between tension in the wall and
`sensation14 is also more complex and, as indicated in the
`previous discussion, requires more thorough study. When a
`compliance curve is shifted to the left or right with no
`change in volume but a change in pressure, a simple appli-
`cation of Laplace’s law would suggest that there has been a
`change in wall tension. Such a change may not be identified
`if only the slope of a linear model is applied to the compli-
`ance curve.
`
`ISOVOLUMETRIC STIMULATION: RELAXATION VERSUS
`ANTINOCICEPTION
`Another pitfall in the interpretation of data in the literature
`pertains to observations with isovolumetric stimuli. These
`volume based mechanical stimuli are vulnerable to misin-
`terpretation; thus changes in wall tension or relaxation will
`result in greater volumes required to achieve the threshold
`of sensation. At first glance, this would suggest a true sen-
`sory eVect of the perturbation or drug. However, as is
`shown from a recent example in the literature,46 volume
`based mechanical stimuli are vulnerable because changes
`in compliance or relaxation are associated with greater vol-
`umes to achieve threshold, but no such change in the pres-
`sure thresholds. In a study of IBS patients, Delvaux and
`colleagues46 demonstrated that alosetron 0.25 mg twice
`daily or 4 mg twice daily was associated with increases in
`the perception threshold and pain threshold to volume dis-
`tensions. However, there was no significant diVerence in
`pressure thresholds, suggesting absence of an antinocicep-
`tive action of alosetron. Studies of colonic compliance per-
`formed in the same evaluation provide an explanation for
`the observed diVerences in volume thresholds as alosetron
`significantly altered the compliance of the colon. Other
`data suggest that relaxation alone is unlikely to result in
`reduced sensation. For example, in a study by Tack and
`colleagues47 performed in 18 healthy volunteers who were
`pretreated for five days with cisapride 10 mg four times
`daily or placebo, the accommodation response of the
`stomach was significantly greater with cisapride. However,
`cisapride did not alter the pressure or volume of first per-
`ception and it actually decreased pain thresholds to both
`volume and pressure stimuli relative to placebo in the fast-
`ing state.
`Surveying the literature, there are several other examples
`(table 1)
`in which drugs have been demonstrated
`unequivocally to reduce sensation to volume distension but
`eVects on pressure induced discomfort have either not
`been evaluated or have not been as clearly demonstrated as
`eVects on volume distension. Examples of altered volume
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`Visceral hypersensitivity
`
`129
`
`Table 1 Pharmacological modulation of visceral tone: documented and
`potential sensory eVects
`
`Agent
`
`Action
`
`Reduced sensation or
`increased pain threshold to
`
`Volume
`distension
`
`Pressure
`distension
`
`Atropine51 52
`CCK51
`5-HT3 antagonists
`OND53 54
`GRA48
`ALO46
`5-HT1 agonists49 55
`
`Octreotide40 45
`
`♡2 Agonist20 26
`Fedotozine50
`Cisapride47
`
`fl Colonic tone
`No eVect on tone
`
`?
`?
`
`+
`+
`+
`+
`
`fl Colonic tone pm
`No change in compliance
`fl Colonic tone,› compliance
`fl Colonic and gastric fasting,
`and pm tone
`fl Colonic pm tone,› phasic
`contractions
`fl Colonic tone,› compliance
`?
`+
`No change in compliance
`fl Gastric tone pm. ?flcompliance −
`
`+
`
`?
`?
`
`?
`?
`?
`?
`
`?/+
`
`+
`+
`−
`
`pm, post meal; CCK, cholecystokinin; OND, ondansetron; GRA, granisetron;
`ALO, alosetron.
`?, unknown; +, reduced sensation; −, increased sensation
`
`thresholds include eVects of ondansetron and granisetron,
`5-HT3 antagonists,48 alosetron (as described above46)
`octreotide,43 sumatriptan,49 and cisapride.47 In contrast,
`there is good evidence that the ♡
`2 adrenergic agonist cloni-
`dine increases compliance of the colon, reduces colonic
`tone, and also markedly reduces pain sensation during
`mechanical distension of the descending colon.26 Similarly,
`the kappa opioid agonist fedotozine50 reduces sensation to
`both volume and pressure stimuli, suggesting it has antino-
`ciceptive activity. The role of cytokines, purines, neuro-
`kinins, and other mediators on sensation and compliance
`requires further study in animals and humans.10
`DiVerences between relaxant and antinociceptive ac-
`tions were demonstrated convincingly in comparisons
`between the eVects of nitroglycerin and clonidine in gastric
`physiology in humans.20 Both these classes of drugs result
`in relaxation of the stomach during fasting and postprandi-
`ally. However, whereas clonidine reduced the sensation of
`pain in a dose dependent manner no such eVect of
`nitroglycerin was observed. In fact, healthy volunteers
`exposed to nitroglyercin tended to have a greater sensation
`of nausea. The selective antinociceptive activities of cloni-
`dine were also demonstrated in experiments performed in
`the human descending colon. Thus whereas
`saline
`(placebo) was associated with a stepwise, intensity related
`perception of gas and pain, clonidine markedly diminished
`the median sensation score for pain, and the ♡
`2 antagonist
`yohimbine increased pain sensation.26 Intriguingly, neither
`clonidine nor yohimbine significantly altered the sensation
`of gas relative to saline placebo. These findings suggest that
`clonidine has a selective eVect on nociceptive pathways26
`rather than on all aVerents.
`
`CEREBRAL BLOOD FLOW MEASUREMENTS
`Changes in cerebral blood flow during viscus stimulation
`require further study. Positron emission tomography and
`functional magnetic resonance imaging are the most widely
`used techniques. After intravenous injection of a radio-
`active compound, positron emission tomography assesses
`blood flow or regional cerebral metabolism in brain areas.
`Functional magnetic resonance imaging detects increases
`in oxygen concentration in areas of heightened neuronal
`activity without administration of radioactive compounds.
`For a more extensive review of these techniques, their
`advantages and limitations, the reader is referred to Aziz
`and Thompson.56 It has been demonstrated that changes in
`cerebral blood flow or evoked potentials are associated with
`viscus sensations or contractions.57 58It is also assumed that
`changes in cerebral blood flow reflect a change in cerebral
`
`control of sensory function23 but little is known of the
`transmitters involved or the sensitivity of changes in blood
`flow relative to perception. One of the most intriguing
`observations has been activation of a focus in the left dor-
`solateral prefrontal cortex in patients with IBS. Thus in a
`landmark study by Silverman et al in 1996, six patients with
`IBS were found to have activation of the left dorsal lateral
`prefrontral cortex in anticipation of a painful rectal stimu-
`lus.27 Cerebral blood flow in these patients was diVerent
`from that of healthy controls in two respects. Firstly, there
`was no activation of the anterior cingulate cortex and sec-
`ondly, there was no focal change in blood flow during the
`actual painful rectal stimulus in patients with IBS. Selective
`activation of the left dorsolateral prefrontal cortex in
`anticipation of the painful stimulus suggests a change in
`attention or vigilance as this part of the brain is involved in
`focus, attention, anticipation, vigilance, and memory
`recall.27
`The initial observations have also been confirmed in
`another study59 that demonstrated activation of the same
`focus of the frontal cortex in patients with IBS or fibro-
`myalgia. Interestingly, the rectal distension stimulated this
`region in IBS patients but not in healthy controls or in
`those with fibromyalgia. In contrast, the left dorsolateral
`prefrontal cortex was activated in fibromyalgia patients fol-
`lowing somatic stimulation, but not following rectal stimu-
`lation. Taken together, these two studies suggest that
`attention and vigilance are activated in anticipation and in
`response to specific stimuli that may be related to patient
`recall as the location of the stimulus is relevant to the
`patient’s symptoms.
`While these changes in cerebral blood flow are extremely
`interesting, it is important to note that several factors may
`influence such changes. Indeed, during somatic painful
`stimuli,
`it has been demonstrated that attention or
`vigilance,60 the unpleasantness61 experience of the stimulus,
`gender,62 and even facial expression63 may influence the
`intensity of changes of cerebral blood flow, as well as the
`locus of that change. For example, Bushnell and col-
`leagues60 have shown that, during imposed attention by
`enhancing a somatic stimulus with a thermal task, there
`was significant activation of the somatosensory cortex. In
`contrast, during application of the painful somatic stimulus
`on its own or during an auditory task, there was no such
`somatosensory cortex activation. This partly explains the
`previous literature in which human brain imaging studies
`did not consistently reveal pain related activation of the
`somatosensory cortex. It also suggests that somatosensory
`cortex activation is highly modulated by cognitive factors
`that alter pain perception, including attention and previous
`experience.
`The perceived u