Gastroenterology 2024;166:976–994

REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY

AND PERSPECTIVES
REVIEWS

AND HEPATOLOGY
Chronic Visceral Pain: New Peripheral Mechanistic Insights and
Resulting Treatments
Alexander C. Ford,1,2,* Stephen Vanner,3,* Purna C. Kashyap,4 and Yasmin Nasser5
1
Leeds Institute of Medical Research at St. James’s, University of |Leeds, Leeds, United Kingdom; 2Leeds Gastroenterology
Institute, Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom; 3Gastrointestinal Diseases Research
Unit, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada; 4Division of Gastroenterology and Hepatology,
Department of Medicine, Mayo Clinic, Rochester, Minnesota; and 5Snyder Institute for Chronic Diseases, Department of
Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

Chronic visceral pain is one of the most common reasons Chronic visceral pain is a hallmark of some DGBI, which
for patients with gastrointestinal disorders, such as in- affect up to 40% of adults, primarily women, worldwide.6
flammatory bowel disease or disorders of brain-gut inter- The diagnosis and treatment of chronic visceral pain is
action, to seek medical attention. It represents a difficult, largely because it is poorly localized and difficult to
substantial burden to patients and is associated with anx- describe due to the relatively small density of nerve ter-
iety, depression, reductions in quality of life, and impaired minals in the viscera and the divergent projections into the
social functioning, as well as increased direct and indirect spinal cord,7 and because the pathophysiology remains
health care costs to society. Unfortunately, the diagnosis incompletely understood. Chronic visceral pain is, thus, a
and treatment of chronic visceral pain is difficult, in part significant burden to patients and is associated with anxiety,
because our understanding of the underlying pathophysi- depression, decreased quality of life, and increased direct
ologic basis is incomplete. In this review, we highlight
and indirect health care costs.5,8,9 IBS alone is estimated to
recent advances in peripheral pain signaling and specific
cost the United States (US) wUS $350 million each year for
physiologic and pathophysiologic preclinical mechanisms
outpatient clinic visits, not including diagnostic testing,
that result in the sensitization of peripheral pain pathways.
medications, nonpharmacologic therapies, or indirect costs
We focus on preclinical mechanisms that have been
translated into treatment approaches and summarize the due to lost productivity.10 Unfortunately, these challenges
current evidence base for directing treatment toward these have been further amplified by the opioid crises.11,12 This
mechanisms of chronic visceral pain derived from clinical highlights the continued need for advances in understand-
trials. The effective management of chronic visceral pain ing of the pathophysiology of visceral pain to enable both
remains of critical importance for the quality of life of effective and safe therapies.
suffers. A deeper understanding of peripheral pain mech- Chronic visceral pain is a disorder of the microbiota-gut-
anisms is necessary and may provide the basis for novel brain axis, and central and peripheral mechanisms both
therapeutic interventions. contribute to its pathogenesis (Figure 1). Triggers include
stress, psychological comorbidities, such as anxiety or
depression, diet, low-grade intestinal inflammation, and
Keywords: Visceral Pain; Inflammatory Bowel Disease; Irritable microbial dysbiosis.4,13–15 Most abdominal pain signaling
Bowel Syndrome; Histamine; Serotonin; Microbiome; Abdom-
inal Pain; Inflammation.
*Authors share co-first authorship.

P ain, defined as an unpleasant sensory and emotional

experience associated with or resembling that
associated with actual or potential tissue damage, can be
Abbreviations used in this paper: HT, 5-hydroxytryptamine; CB1, canna-
binoid receptor 1; cGMP, guanosine 30 ,50 -cyclic monophosphate; DGBI,
disorders of gut-brain interaction; DOR, d-opioid receptor; FD, functional
dyspepsia; FDA, Food and Drug Administration; FMT, fecal microbial
transplant; FODMAP, fermentable oligosaccharides, disaccharides,
acute or chronic.1 It can originate from somatic (muscle, monosaccharides and polyols; GABA, g-aminobutyric acid; GC-C, gua-
bone, or soft tissue) or visceral (thoracic, abdominal, or nylate cyclase-C; GPCRs, G protein-coupled receptors; IBD, inflammatory
bowel disease; IBS, irritable bowel syndrome; IBS-D, inflammatory bowel
pelvic organs) structures.1 Visceral pain is one of the most disease with diarrhea; KOR, k-opioid receptor; MOR, m-opioid receptor;
challenging clinical conditions facing patients and their RCT, randomized controlled trial; SCFA, short-chain fatty acid; SNRI, se-
health care providers. It is extremely common. Abdominal rotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin re-
uptake inhibitor; TCA, tricyclic antidepressant; TRP, transient receptor
pain is a key reason that patients with gastrointestinal potential; TRPV1, transient receptor potential vanilloid 1; US, United
disorders, such as inflammatory bowel disease (IBD) or States.
disorders of gut-brain interaction (DGBI), including irritable Most current article
bowel syndrome (IBS) or functional dyspepsia (FD), seek © 2024 The Author(s). Published by Elsevier Inc. on behalf of the AGA
medical attention.2,3 More than 70% of patients with IBD Institute. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
experience abdominal pain during an acute flare,4 and be- 0016-5085
tween 20% and 60% report chronic abdominal pain.5 https://doi.org/10.1053/j.gastro.2024.01.045
June 2024 Mechanisms of Visceral Pain and Treatment 977

AND PERSPECTIVES
REVIEWS
Figure 1. Chronic visceral pain is a disorder of the gut-brain axis. Nociceptors have cell bodies that lie in the dorsal root ganglia
(DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second-order neurons in
the spinal cord and with central ascending pathways thereafter. Nociceptive neurotransmission in the spinal cord is modulated
by descending pathways. (Inset) At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemo-
sensitive and are stimulated by luminal factors (eg, microbial products and nutrients) as well as by host mediators released due
to infection, inflammation, or tissue damage (eg, serotonin, histamine, proteases, chemokines, and cytokines). These medi-
ators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in
the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

originates from nociceptors (pain-sensitive neurons), called domain potassium channel family, the degenerin/epithelial
visceral primary afferent nerves, whose cell bodies lie in the sodium channel family, including the acid-sensing ion
dorsal root ganglia and which have pseudo-unipolar axons channels 1, 2, and 3, and the piezo-type mechanosensitive
connecting the intestine and the spinal cord.16 Nociceptors ion channel component 2 (Piezo-02).21,22
synapse with second-order neurons in the thoracolumbar Nociceptors at the mucosal level are also chemosensitive
and lumbosacral spinal cord17 and thereafter with central and are stimulated by luminal factors, such as microbial
ascending pain pathways. Nociceptive neurotransmission in products and nutrients, as well as by chemical mediators
the spinal cord is modulated by descending pathways released during tissue infection, inflammation, or damage.
originating from the hypothalamus and midbrain.18 These include bacterial toxins, neurotransmitters, proteases,
Sensitization of nociceptors, defined as a decrease in the bioactive amines, such as histamine, and serotonin, neuro-
threshold for stimulation and an increase in the magnitude of trophins, adenosine-50 -triphosphate, chemokines, and cytokines
the response,19 can occur peripherally, in the central nervous (Figure 1, inset).13,23 Luminal products can either stimulate
system, or both. This results in hyperalgesia, a heightened nociceptors directly, particularly if there is associated break-
response to painful stimuli, and allodynia, which is pain arising down in the mucosal barrier as seen in both IBD and IBS,24,25
from nonpainful stimuli.19 Central sensitization may also result or indirectly via the epithelium or enteroendocrine cells.26
in comorbid pain involving different organ systems,20 a dis- Chemical compounds and luminal products can, in
cussion of which is beyond the scope of this review. turn, stimulate pronociceptive G protein-coupled re-
At the level of the periphery, nociceptive nerve terminals ceptors (GPCRs) or lead to increased expression and
are found in muscle and serosa as well as in the mucosa.7 activation of ion channels, such as TRP or voltage-gated
Nociceptors are mechanosensitive and are stimulated by sodium and calcium channels, or can decrease potassium
stretch or distention.16 These actions are mediated by a channel activation and expression, resulting in peripheral
variety of mechanosensitive ion channels, such as the sensitization. In turn, nociceptors can release neuro-
transient receptor potential (TRP) receptors, including TRP transmitters, such as substance P and calcitonin gene-
vanilloid 1 (TRPV1) and 4, and TRP ankyrin 1, the 2-pore related peptide, which augment the inflammatory
 978 Ford et al Gastroenterology Vol. 166, Iss. 6

response in the periphery and activate second-order clinical effects of GC-C agonists. We note that a recent study
AND PERSPECTIVES

neurons in the spinal cord, leading to neurogenic inflam- has challenged the dogma that enterocyte-derived cGMP is
mation13,23 (Figure 1, inset). the main antinociceptive mediator of GC-C activation,36 as
REVIEWS

Building on this pathophysiological framework, this re- discussed in section 6.

view will focus on recent advances in visceral peripheral Clinical trials. Linaclotide and plecanatide have been
pain neurotransmission and mechanisms that result in tested in multiple randomized controlled trials (RCTs) in IBS
sensitization of afferents in patients with IBD or painful with constipation, summarized in a prior meta-analysis (for
DGBI. It will discuss specific physiologic and pathophysio- summary of all trials discussed see Table 1).37 Both were
logic preclinical peripheral mechanisms that have been more efficacious than placebo in the effect on abdominal pain,
translated into receptor-based treatment approaches for according to the US Food and Drug Administration (FDA)-
visceral pain in clinical trials. Some of these treatments have recommended end point for abdominal pain in IBS with
targeted advances in the physiology of nociceptors or constipation, consisting of a 30% improvement from
intermediary cells, or both, whereas others target new un- baseline for 50% of weeks. However, delayed-release forms
derstanding of pathophysiologic mechanisms of specific of linaclotide, developed based on the premise that ileocecal
disorders. delivery of the drug targets abdominal pain without affecting
bowel habit, were not superior to placebo over most
abdominal pain measures in a phase II RCT.38
Mechanistic Advances and the
Resulting Therapies Peripherally Acting Opioids and Visceral Pain
Guanylate Cyclase-C and Visceral Pain Pharmacology and preclinical studies. Opioids
Guanylate cyclase-C pharmacology and preclinical signal through 4 GPCRs: m-opioid receptors (MORs), d-
studies. The enterocyte receptor guanylate cyclase-C opioid receptors (DORs), k-opioid receptors (KORs), and
(GC-C) plays an essential role in fluid secretion, barrier nociceptin opioid receptors.39 The analgesic effect of con-
function, and nociception. Drugs such as linaclotide and ventional opioids can be strong (eg, oxycodone, morphine)
plecanatide have taken advantage of this homeostatic sys- or weak (eg, codeine) and predominantly result from acti-
tem to treat visceral pain. GC-C is found on the apical sur- vation of MORs, although DORs and KORs also play a role.
face of enterocytes throughout the gastrointestinal tract and On nociceptors, these receptors trigger GPCR-Gi/o protein
is activated by the paracrine hormones uroguanylin and signaling leading to the recruitment of multifunctional
guanylin.27 Activation of GC-C triggers enzymatic conversion intracellular proteins, called b-arrestins, and sustained
of guanosine-5ʹ-triphosphate to guanosine 30 ,50 -cyclic signaling by endosomes.40 This signaling modulates ion
monophosphate (cGMP), which in turn regulates activity of channels and, ultimately, inhibits action potential firing.
the apical cystic fibrosis transmembrane conductance Receptor expression is increased in inflammatory condi-
regulator, leading to increased luminal chloride and bicar- tions, including active IBD, possibly leading to altered
bonate secretion and a secondary increase in intestinal signaling.41
motility.27 Genetic mutations in the guanylate cyclase 2C Conventional opioids can exhibit potent analgesic ac-
gene (GUCY2C) have been found in patients with congenital tions, particularly for acute pain, but are limited by their
secretory diarrhea28 and may predispose patients to IBD,29 adverse effect profile, including cognitive impairment, res-
whereas dysregulated GC-C expression has been implicated piratory depression, nausea, constipation, and addictive
in the pathophysiology of both IBD30 and IBS.31 Sex differ- potential.42 Analgesic tolerance leads to dose escalation and
ences have not been reported.32 consequently greater risk of these potentially life-
Epithelial GC-C signaling has a key role in nociception. threatening adverse effects. Dose escalation is also impli-
Linaclotide, a minimally absorbed GC-C agonist, decreased cated in the development of a paradoxical switch in
the visceral motor response to colorectal distention in both signaling, leading to opioid-induced hyperalgesia, a poorly
acute colitis and stress-induced models of visceral hyper- understood condition.43 The opioid crisis has hastened the
sensitivity. The effects of linaclotide were abolished in GC- search for safer alternatives, including peripherally
C–knockout animals, confirming its specificity.33 Linaclo- restricted opioids that lack addictive potential and central
tide34 or direct application of cGMP34,35 to an ex vivo adverse effects such as respiratory depression and cognitive
preparation of nociceptor afferents decreased response to impairment.
circumferential stretch in control animals as well as in acute Strategies to develop peripherally acting opioids are
colitis35 and in postinflammatory34 models of visceral pain. being explored to identify safe, yet effective, analgesics for
GC-C expression was not found on nociceptors,34,35 sug- visceral pain. Access to the central nervous system can be
gesting its antinociceptive effects were indirect. Indeed, restricted, for example, by creating charged molecules, and
linaclotide34 and uroguanylin35 both stimulated cGMP several compounds display peripheral analgesic actions,44,45
release from cultured epithelial cells.35 The effects of lina- including loperamide, a MOR agonist.46 To date, however,
clotide were abolished in ex vivo preparations where the these do not exhibit sufficient analgesic effects to be clini-
mucosa was removed.34 cally useful to treat visceral pain.
These studies suggest that epithelial GC-C activation Another strategy is to target opioid receptor hetero-
causes basolateral cGMP secretion, which decreases noci- dimers, such as eluxadoline,47 a MOR agonist and DOR
ceptor activity, providing a biological mechanism for the antagonist with weak affinity for KORs. MORs and DORs are
Table 1.Summary of Evidence for Efficacy of Available Treatments Directed Against Peripheral Mechanisms of Abdominal Pain in Their Effect on Abdominal Pain as an End

June 2024
Point

No. of
Treatment studied Condition No. of studies patients Comparator Reported effect

Linaclotide, 290 mg q.d. IBS-C 3 RCTs summarized in a meta- 2447 Placebo RR of abdominal pain persistence ¼ 0.79 (95%
analysis37 CI, 0.73–0.85)
Plecanatide, 6 mg or 3 IBS-C 2 RCTs summarized in a meta- 2194 Placebo RR of abdominal pain persistence ¼ 0.84 (95%
mg q.d. analysis37 CI, 0.78–0.90) and 0.87 (95% CI, 0.81–0.93),
respectively
Loperamide IBS-D 2 RCTs54,55 24 Placebo Abdominal pain score 3.0 vs 0.14, P < .05
Unselected patients 60 Placebo 2.2 days with abdominal pain vs 8.3 days,
with IBS P < .01
Eluxadoline, 100 mg or IBS-D 4 RCTs summarized in a meta- 2758 Placebo RR of abdominal pain persistence ¼ 0.89 (95%
75 mg b.i.d. analysis56 CI, 0.83–0.96) and 0.95 (95% CI, 0.88–1.04),
respectively
Psyllium (up to 10 g/d) Unselected patients 2 RCTs89,90 80 Placebo Abdominal pain mild or absent in 52.5% vs
with IBS 178 Placebo 57.5%, N/S
RR of adequate relief of abdominal pain at 1, 2,
and 3 months ¼ 1.60 (95% CI, 1.13–2.26),
1.44 (95% CI, 1.02–2.06), and 1.36 (95% CI,
0.90–2.04), respectively
Bran (up to 10 g/d) Unselected patients 1 RCT90 190 Placebo RR of adequate relief of abdominal pain at 1, 2,
with IBS and 3 months ¼ 1.13 (95% CI, 0.81–1.58),
1.22 (95% CI, 0.86–1.72), and 1.70 (95% CI,
1.12–2.57), respectively
Low FODMAP diet IBS 12 RCTs summarized in a 914 BDA dietary advice RR of abdominal pain persistence ¼ 0.78 (95%

Mechanisms of Visceral Pain and Treatment

IBD meta-analysis91 52 Habitual diet CI, 0.57–1.06)
2 RCTs92,93 89 Sham diet RR of abdominal pain persistence ¼ 0.72 (95%
Sham diet CI, 0.47–1.10)
Habitual diet RR of abdominal pain persistence ¼ 0.51 (95%
CI, 0.30–0.87)
Abdominal pain severity score 22 vs 30, P ¼
.098 and 36 days with abdominal pain vs 38
days, P ¼ .78
OR for improvement in abdominal pain
frequency ¼ 2.97 (95% CI, 1.12–7.89)
Rifaximin, 550 mg t.i.d. Nonconstipated IBS 2 RCTs summarized in a meta- 1260 Placebo RR of abdominal pain persistence ¼ 0.95 (95%
for 2 weeks analysis56 CI, 0.89–1.01

979
REVIEWS
AND PERSPECTIVES
 AND PERSPECTIVES
REVIEWS

Table 1. Continued

980
No. of

Ford et al
Treatment studied Condition No. of studies patients Comparator Reported effect
96,97
FMT IBS with bloating 2 RCTs 62 Placebo Abdominal pain score 2.80 vs 3.88 at baseline
Unselected patients 1 RCT98 165 Placebo with FMT, P ¼ .001, compared with 3.57 vs
with IBS 20 Usual treatment 3.79 at baseline with usual treatment, P ¼
UC .205
Abdominal pain score 166.8 and 186.3
posttreatment with 60 mg and 30 mg FMT,
respectively, vs 307.0 with placebo, P < .001
Abdominal pain score 0.9 vs 4.5 at baseline with
FMT, P ¼ .026, compared with 1.8 vs 4.9 at
baseline with usual treatment, N/S
Gelsectan IBS-D 1 RCT99 60 Placebo Number of patients with totally to slightly
unacceptable abdominal pain reduced from
67% at baseline to 0% at 4 weeks with
gelsectan vs 83% to 60% with placebo,
statistical significance not reported
Probiotics All in unselected 32 RCTs100 3469 Placebo RR of abdominal pain persistence ¼ 0.72 (95%
Combination probiotics patients with IBS 11 RCTs100 1183 Placebo CI, 0.64–0.82)
Lactobacillus- 5 RCTs100 1482 Placebo RR of abdominal pain persistence ¼ 0.59 (95%
containing strains 3 RCTs100 389 Placebo CI, 0.45–0.76)
Saccharomyces 3 RCTs100 212 Placebo RR of abdominal pain persistence ¼ 0.64 (95%
cerevisiae I-3856 CI, 0.45–0.90)
Bifidobacterium- RR of abdominal pain persistence ¼ 0.78 (95%
containing strains CI, 0.64–0.95)
Bacillus-containing RR of abdominal pain persistence ¼ 0.33 (95%
strains CI, 0.23–0.47)
Ketotifen (titrated from Unselected patients 1 RCT109 60 Placebo 7% of patients reporting severe abdominal pain
2 mg to 6 mg b.i.d.) with IBS vs 28%, P ¼ .02
Ebastine 20 mg o.d. Unselected patients 1 RCT110 55 Placebo Relief of abdominal pain in 41% vs 20%, P ¼ .19
with IBS 1 RCT111 202 Placebo 30% improvement in abdominal pain in 37%
Nonconstipated IBS vs 25%, P ¼ .081
Disodium IBS-D 1 RCT112 43 No treatment 50% improvement in abdominal pain in 77%

Gastroenterology Vol. 166, Iss. 6

cromoglycate, 600 vs 28%, P ¼ .002
mg/d
Peppermint oil (usually Unselected patients 7 RCTs summarized in a meta- 748 Placebo RR of abdominal pain persistence ¼ 0.76 (95%
2 capsules t.i.d.) with IBS analysis119 CI, 0.62–0.93)
Table 1. Continued

June 2024
No. of
Treatment studied Condition No. of studies patients Comparator Reported effect
120
Red pepper (capsaicin) Unselected patients 1 RCT 50 Placebo Abdominal pain score 1.9 vs 2.7 at baseline with
with IBS 1 RCT121 30 Placebo red pepper, compared with 2.3 vs 2.4 at
FD baseline with placebo, reported as
“statistically significant”
Abdominal pain score 1.61 posttreatment vs
2.37, P < .05
Alosetron, 1 mg b.i.d. IBS-D 6 RCTs summarized in a meta- 2606 Placebo RR of abdominal pain persistence ¼ 0.83 (95%
analysis56 0.78–0.88)
Ramosetron, 5 mg or IBS-D 5 RCTs summarized in a meta- 1928 Placebo RR of abdominal pain persistence ¼ 0.82 (95%
2.5 mg o.d. analysis56 CI, 0.75–0.89) and 0.75 (95% CI, 0.65–0.85),
respectively
Ondansetron, 12 mg IBS-D 3 RCTs summarized in a meta- 327 Placebo RR of abdominal pain persistence ¼ 0.95 (95%
q.d, bimodal release analysis127 CI, 0.74–1.20)
or titrated up or
down from 4 mg
o.d.
Tegaserod, 6 mg b.i.d. IBS-C Pooled analysis of 4 RCTs128 2886 Placebo OR for abdominal pain response ¼ 1.38 (95%
FD 2 RCTs129 1360 Placebo CI, 1.14–1.67)
1307 Placebo Abdominal pain response rate 44.9% vs 40.0%,
P ¼ .027
Abdominal pain response rate 44.0% vs 42.3%,
P ¼ .51
SSRIs (eg, Unselected patients 5 RCTs summarized in a meta- 262 Placebo RR of abdominal pain persistence ¼ 0.82 (95%
escitalopram, 10 mg with IBS analysis132 195 Placebo CI, 0.58–1.16)

Mechanisms of Visceral Pain and Treatment

o.d.) FD 1 RCT133 Upper abdominal pain score 1.4 posttreatment
vs 1.2, N/S
TCAs (eg, amitriptyline, Unselected patients 4 RCTs summarized in a meta- 171 Placebo RR of abdominal pain persistence ¼ 0.53 (95%
10–30 mg o.d., or with IBS analysis132 463 Placebo CI, 0.34–0.83)
imipramine, 50 mg FD 1 RCT134 194 Placebo OR for 30% improvement in abdominal pain ¼
o.d.) 2 RCTs133,135 107 Placebo 1.66 (95% CI, 1.12–2.46)
Upper abdominal pain score 1.1 post-treatment
vs 1.2, N/S
Epigastric pain score 0.96 vs 1.24 at baseline
with imipramine, P ¼ .026, compared with
0.96 vs 1.13 at baseline with placebo, P ¼
.13
SNRIs (eg., venlafaxine Unselected patients 1 RCT136 30 Placebo Frequency of abdominal pain or discomfort
150 mg o.d.) with IBS score 3.87 vs 4.93, P ¼ .03

981
REVIEWS
AND PERSPECTIVES
 982 Ford et al Gastroenterology Vol. 166, Iss. 6

coexpressed on nociceptors innervating the intestine, and

56.5%, 59.7%, and 56.7% of 10 mg, 25 mg, and

of 4.61 with 25 mg t.i.d. and 4.57 with 100

BDA, British Dietetic Association; b.i.d., twice daily; CI, confidence interval; IBS-C, IBS with constipation; N/A, not applicable; N/S, not significant; o.d., once daily; OR,
50 mg t.i.d., respectively, achieved a 30%

Epigastric pain score 3.0 posttreatment vs 4.0,

Change in abdominal pain score from baseline

Abdominal pain score 28 posttreatment vs 40,

AND PERSPECTIVES

improvement in abdominal pain vs 52.9%

eluxadoline shows high binding affinity for MOR/DOR het-
erodimers in cell assays48 and functional interaction be-
REVIEWS

tween receptors. However, there has been sparse

mechanistic study in whole-animal models to clarify the role
Reported effect

of this interaction further.49

There are other promising strategies to develop safe
opiates, such as enhancing endogenous opioids (eg, enke-
phalinase inhibitors), by developing pH-sensitive opioid
with placebo, N/S

analogues,50 which are only active at sites of inflammation

and thus lack the adverse effect profile and addictive po-
tential of conventional opioids. Combinations of subthresh-
P ¼ .008
mg t.i.d.

P ¼ .01 old opioids and cannabinoid receptor 1 (CB1) agonists can

provide strong analgesia51 without adverse effects. Novel
delivery systems using nanoparticles of between 1 and 100
nm in diameter, containing opioid cargoes,52 target intra-
cellular signaling in endosomes and can be delivered
intrarectally to act locally within the inflamed colon. To
Comparator

date, most of these strategies are based on preclinical

studies and none have been tested adequately in humans.
Finally, female rodents are less sensitive to opiate anal-
Placebo

Placebo
Placebo

gesia,53 and whether these strategies have sex-specific ef-

N/A

fects would be important to evaluate.

Clinical trials. Few trials have been conducted with
new opioid-related drugs in visceral pain, largely due to the
negative impact of the opioid crisis. Despite widespread use
patients

of loperamide in clinical practice, there is little evidence for

No. of

273

85
14

72

this. One 13-week RCT, recruiting patients with IBS with

diarrhea (IBS-D), reported pain scores were significantly
lower with loperamide.54 In a second 3-week trial that
recruited IBS of all subtypes, the number of painful days
was reduced significantly with loperamide, but only in pa-
tients with alternating bowel habit.55 Both trials used his-
torical definitions of IBS, did not conform to guidance for
1 randomized, open-label

design of treatment trials in DGBI, and many participants

No. of studies

did not report abdominal pain at all. More rigorous trials of

loperamide are needed, although it is unlikely these will
odds ratio; q.d., once daily; RR, relative risk; t.i.d., 3 times daily.

ever be conducted.
study148

In contrast, eluxadoline has been tested rigorously in

147

1 RCT154
1 RCT155

phase III RCTs at 2 doses, 75 mg or 100 mg twice daily, with

1 RCT

data pooled in a prior meta-analysis.56 Only 100 mg twice

daily was superior to placebo for the FDA-recommended
end point for abdominal pain, but benefit was modest. In
addition, there have been safety issues, with episodes of
Crohn’s disease with

Unselected patients
IBS with abdominal

acute pancreatitis and sphincter of Oddi dysfunction

abdominal pain
Condition

reported.
with IBS
pain

The Microbiome and Visceral Pain

Advances in pathophysiology. The involvement of
FD

gut microbiota in the development of visceral pain is largely

based on preclinical studies measuring pain thresholds after
Pregabalin, 75 mg o.d.,

transfer of human stool microbiota into germ-free rodents

Treatment studied

or titrated up from
Table 1. Continued

Oloroinab, 10 mg to

or administration of live biotherapeutics (probiotics) or

100 mg t.i.d.

antibiotics, or both, in rodent models. For instance, germ-

75 mg b.i.d.

free rats colonized with stool microbiota from individuals

with IBS display decreased pain thresholds in response to
rectal distention.57 Further insights have been gained from
studies involving gnotobiotic mice, revealing the role of
June 2024 Mechanisms of Visceral Pain and Treatment 983

commensal microbes in maintaining normal excitability of dopamine, initiate the adrenoceptor alpha 2A (Adra2A) and

AND PERSPECTIVES
gut intrinsic neurons.58 the transient receptor potential cation channel subfamily C

REVIEWS
Perturbing the gut microbiome during early life using member 4 (TRPC4) signaling cascade.
vancomycin leads to visceral hypersensitivity in rats.59 On the other hand, short-chain fatty acids (SCFAs) and
Conversely, administration of live biotherapeutics, such as branched-chain fatty acids, such as isovaleric acid and, to a
Faecalibacterium prausnitzii, Lactobacillus paracasei lesser extent, butyrate, activate the olfactory receptor 558
NCC2461, or Lactobacillus GG, reduces visceral hypersensi- and P/Q type Cav channel within enterochromaffin cells.68 A
tivity and intestinal permeability in preclinical models that multitude of bacterial metabolites, including butyrate, also
alter the early-life microbiome.60,61 Unlike in early life, augment serotonin synthesis within enterochromaffin
antibiotic administration improves visceral hypersensitivity cells.69 The role played by serotonin in modulating visceral
in adult mice,62 suggesting potential age-dependent effects pain, as well as the critical role of enterochromaffin cells in
of the microbiome. isovalerate-induced visceral hypersensitivity, is discussed
Interestingly, visceral pain responses to colorectal further below.
distention vary across the estrous cycle in female mice, but Pathogen-associated molecular pattern molecules, which
this effect is lost in germ-free animals. Ovariectomy caused include bacterial cell wall components such as lipopolysac-
visceral hypersensitivity in specific pathogen-free, but not charide, bind to pattern recognition receptors such as Toll-
germ-free mice, suggesting an interaction between sex like receptors, are present on immune cells and sensory
hormones, visceral pain, and the microbiome.63 neurons. Pathogen-associated molecular pattern molecules
Building on insights from animal models, human studies contribute to visceral hypersensitivity by influencing noci-
exploring fecal microbiome changes in patients with IBS ceptors directly or by affecting immune cells indirectly,
have found specific taxa that positively (Proteobacteria)64 leading to peripheral sensitization.70,71 Diet-derived me-
or negatively (Bifidobacterium spp) correlate with the tabolites from bacterial fermentation, such as SCFAs, indole
severity of pain.65 Although human microbiome studies and indole derivatives, and kynurenine, also modulate
have focused largely on the colon, changes in small- visceral nociception. Butyrate exerts antinociceptive ef-
intestinal microbial composition, rather than bacterial fects72 via peroxisome proliferator-activated receptors
numbers, appear to differentiate patients with abdominal suppressing the activity of nuclear factor k-light-chain-
pain from healthy controls.66 However, the role of small- enhancer of activated B cells, involved in pain and
intestinal microbiota in the pathophysiology of abdominal inflammation.73,74
pain remains unclear. Together, although findings from Butyrate also augments intestinal barrier function via
preclinical models and human studies underscore a role of activation of hypoxia inducible factor,75 regulates immune
the gut microbiome, whether these changes are causal to the cells via free fatty acid 2/3 receptors,76 and drives epige-
development of visceral hypersensitivity or a consequence netic changes. Tryptophan is converted by microbes to
of changes in diet and gastrointestinal motility is unknown. kynurenic acid77 or to indole derivatives,78 both of which
Gut microbiota-derived metabolites, neurotransmitters, exert anti-inflammatory effects via G protein-coupled re-
toxins, and cell wall components have emerged as potential ceptor 35 and aryl hydrocarbon receptor, respectively,79,80
factors underlying the pathophysiology of visceral hyper- Gut bacteria play an important role in determining the
sensitivity. These bioactive compounds can (1) sensitize luminal bile acid and protease pool. Bile acid metabolites,
sensory neurons indirectly by stimulating either enter- including deoxycholic acid, regulate pain through the acti-
oendocrine cells, which release serotonin, or immune cells, vation of G protein-coupled bile acid receptor 1, and are
which release chemokines and cytokines, both of which act present in both primary sensory neurons and macrophages.
on distinct neuronal populations, (2) disrupt the intestinal Proteases contribute to visceral hypersensitivity by target-
barrier, allowing passage of potentially noxious stimuli, and ing intestinal barrier function81 as well as by signaling
(3) activate sensory neurons directly, particularly in in- directly through protease activated receptor 2, present on
stances where barrier function is compromised (Figure 2). neurons.82 The luminal protease pool depends on the bal-
Most bacteria-derived compounds are pleiotropic, acting via ance between bacterial proteases83 and suppression of host
multiple signaling pathways. Thus, they exert wide-ranging proteases by bacteria harboring b-glucuronidases.81
effects. Furthermore, gut microbiota can both synthesize The identification of distinct microbiota-driven mecha-
and use neurotransmitters, encompassing excitatory, such nisms opens the door for novel therapeutic strategies.
as glutamate, histamine, dopamine, and norepinephrine, and Currently, microbiota-targeted interventions largely focus
inhibitory neurotransmitters, such as g-aminobutyric acid on augmenting intestinal barrier function. In preclinical
(GABA).67 These neurotransmitters allow intercommunica- studies, fiber maintained both microbial diversity and bar-
tion among microbiota members and the host. rier function,84 and a diet low in fermentable oligosaccha-
Enterochromaffin cells are the primary cell type rides, disaccharides, monosaccharides and polyols
responsible for peripheral serotonin production. They are (FODMAP) was found to preserve barrier function by
polymodal chemosensors, capable of detecting specific decreasing lipopolysaccharide-mediated mast cell
luminal signals via an array of receptor pathways and activation.85
translating them to the enteric nervous system by modu- Clinical trials. There are a multitude of methods to
lating serotonin-sensitive primary afferent nerves.68 Cate- manipulate the microbiome, and thereby microbial metab-
cholamine neurotransmitters, such as norepinephrine and olites, as a means of treating abdominal pain. SCFA enemas
 984 Ford et al Gastroenterology Vol. 166, Iss. 6

have been studied in IBD, but trials have not reported an stored in high concentrations, predominantly in mast cells,
AND PERSPECTIVES

effect on abdominal pain.86–88 Fiber has been assessed in but also in basophils and eosinophils. However, other cells
IBS, but few trials report abdominal pain outcomes.89,90 One
REVIEWS

in the gut also express histidine decarboxylase, including

12-week RCT found there was no benefit of psyllium, a macrophages, neutrophils, platelets, and dendritic cells, and
soluble fiber, over placebo,89 but in another trial of psyllium, can synthesize and release histamine but do not store it.102
bran, or placebo, significant improvements in abdominal In the lumen of the gastrointestinal tract, there are 3
pain occurred with both psyllium and bran at several time possible sources: synthesis by microbiota, ingestion of
points.90 histamine-rich foods, and histamine released from tissues
A network meta-analysis of 12 trials studied the effect of that permeates into the lumen.
a low FODMAP diet on abdominal pain.91 It was superior to Histamine is metabolized by 2 dominant pathways, his-
a sham diet but was not superior to standard British Dietetic tamine-N-methyltransferase and diamine oxidase,103
Association dietary advice for IBS or habitual diet. In resulting in N-methyl histamine and imidazole acetalde-
contrast, in a RCT comparing a 4-week low FODMAP diet hyde metabolites, respectively. These metabolites also
with a sham diet in patients with quiescent IBD with exhibit biological activity (eg, N-methyl histamine), and the
persistent gastrointestinal symptoms, abdominal pain preponderance of the pathways may differ between mast
severity and days with abdominal pain did not differ.92 In cells and microbiota.
another 6-week trial of a low FODMAP diet vs normal diet in Histamine, and possibly some metabolites, can activate 4
patients with IBD in remission with ongoing gastrointestinal GPCRs, H1 to H4.101 These GPCRs signal intracellularly via
symptoms, response for abdominal pain frequency, but not Gq and cyclic adenosine monophosphate to modulate pas-
severity, was significantly higher with the low FODMAP diet.93 sive and voltage-gated ion channels on nociceptors and
Abdominal pain response rates with rifaximin, a minimally other effector pathways in nonneuronal cells. The distribu-
absorbed antibiotic, according to the FDA-recommended end tion of these receptors within the gut suggests histamine
point, were reported in a meta-analysis.56 There was no activates pain signaling directly through activation of neu-
benefit with rifaximin over placebo. rons and indirectly via immune cell activation (Figure 3).
Although there have been multiple RCTs of fecal micro- In humans,104 H1 receptors are found on connective
bial transplant (FMT) in both IBS and IBD, summarized in tissues cells, immune cells, enterocytes, smooth muscle cells,
prior meta-analyses,94,95 few report impact of FMT on and nerves, H2 receptors are found on gastric parietal cells,
abdominal pain. Two RCTs of FMT in IBS studied this end enterocytes, immunocytes, enteric nerves, and smooth
point.96,97 One 12-week trial of a single FMT via nasojejunal muscle cells, and H4 receptors are expressed on immune
tube in IBS with predominant bloating reported abdominal cells, blood vessels, nerves, and enterocytes. H3 receptors
pain scores were significantly reduced.96 In the second RCT, have yet to be identified in humans.
30 mg or 60 mg of a single FMT via gastroscopy led to a Previous studies highlight the role of histamine in pa-
significant reduction in abdominal pain at 3 months vs tients with IBS, demonstrating increased levels of histamine
placebo.97 One RCT comparing FMT with usual therapy in (and proteases) in mucosal biopsy specimens from patients
active ulcerative colitis reported abdominal pain scores compared with healthy controls, evidence of mast cell acti-
improved significantly with FMT at 2 weeks compared with vation, and the ability of histamine in tissue supernatants
baseline, but also improved significantly in the usual ther- from patients to exaggerate activation of rodent and human
apy arm.98 nociceptive neurons.105 Sex differences have not been
Gelsectan, a prebiotic with mucoprotective and bifido- described. More recent studies show increases in duodenal
genic effects, which may reinforce the intestinal barrier, was eosinophils in patients with FD, another source of tissue
studied in 1 crossover trial.99 The number of participants histamine, implicating a role in abdominal pain in this dis-
with totally to slightly unacceptable abdominal pain was order.106 The triggers resulting in abnormal mast cell-
reduced from baseline to 4 weeks compared with placebo. histamine signaling observed in these patients have been
Finally, in a meta-analysis certain combinations of pro- unclear, but recent preclinical studies suggest multiple
biotics, Lactobacillus-containing strains, Saccharomyces cer- possible etiologies, as outlined below.
evisiae I-3856, and Bifidobacteria- and Bacillus-containing When mice develop a self-limiting bacterial colitis and
strains improved abdominal pain, but certainty in the evi- are exposed simultaneously to a food antigen, and then
dence was low to very low across the studies, with het- reexposed to the food antigen alone after resolution of
erogeneity between individual trials in most analyses.100 infection, they lose oral tolerance to the food antigen.14 This
leads to visceral hypersensitivity and mast cell activation
with histamine release. This exaggerated pain signaling was
Histamine and Visceral Pain blocked by an H1 receptor antagonist, which inhibits hista-
Pharmacology and preclinical studies. Histamine mine signaling to neurons, and by an IgE antibody, which
functions as a paracrine signaling molecule that can activate prevents mast cell activation. Tissues exhibited elevated IgE
nociceptors in the gastrointestinal tract (Figure 3). It is a levels, consistent with loss of oral tolerance, but there was
member of the biogenic amine family and is synthesized no systemic increase in IgE, highlighting immune activation
from L-histidine exclusively by L-histidine decarboxylase.101 was confined to the intestine.
Histamine signaling to nociceptors in the gut could originate Injection of common antigens into the rectal mucosa in
from 2 sources: intestinal tissue or the lumen. In tissue, it is patients with IBS caused greater wheal and flare responses,
June 2024 Mechanisms of Visceral Pain and Treatment 985

AND PERSPECTIVES
REVIEWS
Figure 2. Mechanisms underlying gut microbiome-driven visceral nociception. Gut microbiome-derived products can sensitize
peripheral nociceptors directly or act indirectly by stimulating immune cells or enterochromaffin cells, or both, to release
cytokines, chemokines, or serotonin, or a combination of these, respectively. The gut microbiome can also modulate intestinal
barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate. AHR, aryl hy-
drocarbon receptor; CA, carboxylic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FFAR, free fatty acid re-
ceptor; FXR, farnesoid X receptor; GPR35, G protein-coupled receptor 35; LCA, lithocholic acid; LPS, lipopolysaccharide; LTS,
leukotrienes PAMPs, pathogen-associated molecular patterns; PAR2, protease activated receptor 2; PGN, peptidoglycan;
TGR5, Takeda G protein-coupled receptor 5; TLR, Toll-like receptor.

compared with healthy volunteers, consistent with the hy- relief of abdominal pain were numerically higher with
pothesis that some patients with IBS are sensitized to food ebastine, but not significantly so. In a subsequent phase IIb
antigens.14 Recent preliminary studies suggest psychologi- placebo-controlled trial, rates of abdominal pain improve-
cal stress can also induce loss of oral tolerance to food an- ment were higher with ebastine, although this was not
tigens and lead to mast cell-histamine–mediated visceral significant.111 The effect of the mast cell stabilizer disodium
hypersensitivity in both the small intestine and colon, a cromoglycate on abdominal pain was studied in a RCT in
feature observed in many patients with IBS.107 IBS-D.112 In this 6-month study, compared with no treat-
Histamine production by the microbiota may be stimu- ment, significantly more patients randomized to disodium
lated by poorly absorbed complex carbohydrates. In a study cromoglycate experienced abdominal pain improvement.
using germ-free mice to create a humanized IBS mouse
model with fecal microbiota from patients with IBS and
healthy controls,108 mice given fecal samples from patients Transient Receptor Potential Vanilloid 1 and
with IBS who were high histamine producers, based on stool Visceral Pain
and urine samples, exhibited visceral hyperalgesia. This Pharmacology and preclinical studies. TRPV1 is a
exaggerated pain signaling was blocked by H1- and H4- nonselective ligand-gated cation channel that is highly
receptor antagonists, suggesting several signaling pathways enriched in gastrointestinal tract nociceptors. It is activated
were involved (Figure 3). Some of the histamine in the by polymodal stimuli, including mechanical stretch, noxious
luminal samples could originate from the host (eg, mast cell heat, low pH, exogenous chemical irritants, such as capsaicin
degranulation). However, high histamine producers were (the active ingredient in chili peppers), and endogenous
found to have microbial species, including Klebsiella aero- lipid metabolites of arachidonic acid (eg, the endocannabi-
genes, in their stool that could make up to 100 times more noid anandamide113). Selective ablation of colon-projecting
histamine than those without. TRPV1-expressing neurons decreased nociception in
Clinical trials. Drugs targeting histamine receptors response to colorectal distention in mice,22 highlighting its
or stabilizing mast cells have not been well studied in critical role in visceral pain. Estrogens can modulate
gastrointestinal diseases. An 8-week trial of ketotifen, a lumbosacral dorsal root ganglia TRPV1 expression, sug-
H1-receptor antagonist, in IBS reported a significant gesting a potential mechanism for sex differences in visceral
improvement in abdominal pain over placebo.109 Ebastine, pain.114
another H1-receptor antagonist, has been assessed in Sensitization of TRPV1 by inflammatory mediators, such
IBS.110,111 A 12-week proof-of-concept RCT found rates of as histamine,110 is one of the key pathways in mediating
 986 Ford et al Gastroenterology Vol. 166, Iss. 6

peripheral visceral hypersensitivity, as discussed above. reuptake, and release in IBS,124 suggesting dysregulated
AND PERSPECTIVES

However, TRPV1 expression does not necessarily correlate 5HT signaling contributes to the pathophysiology of visceral
REVIEWS

with receptor sensitization. For example, in patients with pain. Surprisingly, few studies evaluating the role of TCAs in
IBS who were hypersensitive to rectal distention, rectal visceral pain have been performed in rodent models.
application of capsaicin caused increased pain perception. Although 5HT can be secreted by enteric neurons and
No change in TRPV1 expression was noted when comparing mucosal mast cells, most of the body’s 5HT is synthesized
hypersensitive and normosensitive patients with IBS, sug- and stored by enterochromaffin cells.122 Enterochromaffin
gesting that although TRPV1 expression is important, cells are electrically excitable, and display axon-like basal
additional factors, such as receptor sensitization or central processes, forming functional connections with extrinsic
factors, or both, are necessary in mediating visceral pain.115 and intrinsic afferent neurons, termed neuropods.68,125
Although most of the studies have focused on TRPV1 Enterochromaffin cells function as luminal sensory trans-
sensitization in IBS and FD,113 TRPV1 may also play a role in ducers, releasing 5HT in response to dietary nutrients and
chronic visceral pain in patients with IBD in remission. microbial products, as well as mucosal distortion via
Rectal TRPV1 expression was increased in patients with IBD mechanosensitive Piezo-02 channels.126 5HT release by
in endoscopic remission with chronic visceral pain and enterochromaffin cells, thus initiates intrinsic gut reflexes
correlated with patient-reported symptoms.116 Visceral and stimulates extrinsic nerves.
hyperalgesia was TRPV1-dependent in postinflammatory A recent study evaluated the role of a mucosal afferent-
mice,117 and they also displayed increased SCFA-producing enterochromaffin cell circuit in the pathogenesis of visceral
microbiota and stool SCFA content. These microbial- hypersensitivity using transgenic mice,26 where entero-
derived SCFAs increased capsaicin-evoked calcium re- chromaffin cells could be activated or silenced selectively.
sponses in the postinflammatory state, suggesting that mi- Direct activation of enterochromaffin cells elicited 5HT
crobial metabolites can sensitize TRPV1.118 release and was sufficient to cause both acute and chronic
Clinical trials. Peppermint oil, as well as being a visceral hypersensitivity to colorectal distention. Remark-
smooth muscle relaxant, may have effects on TRPV1 ably, activation of enterochromaffin cells was sufficient to
signaling. A meta-analysis showed it was more efficacious elicit anxiety-like behavior in mice. These effects were
than placebo for abdominal pain.119 However, benefit was inhibited by the 5HT3 antagonist alosetron, which
modest, with heterogeneity between studies, and most trials decreased mucosal afferent activity. Conversely, silencing
did not use FDA-recommended end points. Although activity of enterochromaffin cells attenuated 5HT release
capsaicin stimulates the TRPV1 receptor, leading to wors- and visceral hypersensitivity mediated by the microbial
ening abdominal pain, repeated administration down- metabolite, isovalerate, in male mice. The mucosal afferent-
regulates the receptor. A 6-week trial in IBS showed enterochromaffin cell circuit demonstrated high tonic ac-
abdominal pain scores were significantly lower, compared tivity in female, but not male, mice suggesting a sex-specific
with baseline, in patients receiving red pepper pills contribution to pain signaling. Together, these data
compared with those receiving placebo.120 A similar 5-week demonstrate that the enterochromaffin cell-mucosal
study in FD demonstrated a significant reduction in afferent circuit plays an essential role in pathogenesis of
epigastric pain scores with red pepper vs placebo.121 visceral hypersensitivity.26
However, patients in both trials randomized to red pepper It is possible that the GC-C pathway also regulates 5HT
dropped out due to pain exacerbations. secretion from enterochromaffin cells. GC-C is expressed not
only by enterocytes but also by a subtype of monoamine
synthesis-expressing neuropods enriched in the proximal
Serotonin (5-Hydroxytryptamine) and Visceral intestine of mice.36 GC-C enriched neuropods formed func-
Pain tional connections with nociceptors in cocultures and caused
Pharmacology and preclinical studies. The mono- spontaneous nociceptor activation, which was abolished by
amine neurotransmitter 5-hydroxytryptamine (5HT) plays linaclotide. The antinociceptive effects of linaclotide on the
an integral role in initiation of intrinsic gut reflexes regu- response to colorectal distention were lost in mice that were
lating motility, secretion, and vasodilation. It also partici- deficient in neuropod GC-C.36 Thus, it is possible that
pates in the pathogenesis of visceral pain via afferent nerve enterochromaffin GC-C activation regulates 5HT tone, but
5-HT3 and 5-HT4 receptors; drugs that modulate these re- whether this mechanism is active in vivo is unclear.
ceptors have been used extensively in the treatment of Clinical trials. The efficacy of the 5HT3-receptor
visceral hypersensitivity.122 The actions of 5HT are termi- antagonists alosetron and ramosetron, according to the
nated by the serotonin selective reuptake transporter, a FDA-recommended end point for abdominal pain, has been
peripheral target of selective serotonin reuptake inhibitors reported in multiple trials in IBS-D, pooled in a meta-
(SSRIs), tricyclic antidepressants (TCAs), and serotonin analysis.56 Ramosetron, 2.5 mg daily and 5 mm daily, and
norepinephrine reuptake inhibitors122 (SNRIs). alosetron, 1 mg twice daily, were superior to placebo,
Genetic polymorphisms in the 5-HT3 receptor and the although alosetron has been associated with ischemic colitis.
serotonergic synthetic enzyme, tryptophan hydroxylase, are Varying doses of ondansetron, another 5HT3-receptor
associated with increased IBS susceptibility, whereas SSRI antagonist with a long history of safety, were assessed in
transporter polymorphisms are associated with both IBS 3 trials in IBS-D, summarized in another meta-analysis.127
and FD.123 Multiple studies report changes in 5HT synthesis, The drug was not superior to placebo for pain.
June 2024 Mechanisms of Visceral Pain and Treatment 987

AND PERSPECTIVES
REVIEWS
Figure 3. Novel mechanisms causing increased histamine signaling to intestinal nociceptors. (A) This schema shows that after
combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress
exposure, reexposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic), causing
mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased
pain signaling. (B) This schema shows that ingestion of poorly absorbed complex carbohydrates (CHO) (eg, FODMAPs) can
stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100 times more histamine than
those lacking this bacterium in their stool samples. Luminal histamine stimulates H4 and H1 receptors, leading to mast cell
degranulation with ensuing nociceptor sensitization and increased pain signaling. DRG, dorsal root ganglia.

For 5HT4-receptor agonists, in a pooled analysis of data frequency scores were reduced significantly compared with
from 4 RCTs in IBS, tegaserod, 6 mg twice daily, was more placebo.136 An RCT of FD did not report its effect on
efficacious for pain than placebo.128 In two 6-week trials of abdominal pain.137
tegaserod in FD, 6 mg twice daily was superior to placebo
for abdominal pain in 1 RCT but not the other.129 Safety Cannabinoids and Visceral Pain
issues arising from cardiovascular and cerebrovascular Pharmacology and preclinical studies. Cannabinoids
ischemic events led to the withdrawal of tegaserod. are widely used alternative therapies to treat abdominal pain
Although it was reintroduced briefly, tegaserod is now no in both IBD and IBS.138,139 The actions of cannabinoids are
longer available. Prucalopride was assessed in chronic mediated via the endocannabinoid system, which regulates
constipation and was efficacious,130 but no RCTs report its gastrointestinal motility, secretion, immune function, in-
efficacy in improving abdominal pain, and it has never been testinal permeability, and visceral hypersensitivity.140
tested in IBS or FD. The classical components of the endocannabinoid
Although SSRIs, TCAs, and SNRIs are antidepressants, in system are the endogenous cannabinoid ligands, ananda-
the context of treating abdominal pain, they act as gut-brain mide, and 2-arachidonoylglycerol, as well as their biosyn-
neuromodulators involving, at least in part, 5-HT131; dis- thetic and degradative enzymes. These are found
cussion of the central actions of these compounds is beyond throughout the microbiota-gut-brain axis, including the
the scope of this review. SSRIs have been assessed in IBS epithelium, enterochromaffin cells, enteric nervous system,
and FD, with no impact on abdominal pain in IBS in a prior and immune system, as well as extrinsic afferent nerves,
meta-analysis,132 and a reduction in pain scores in FD in a where they primarily exert an antinociceptive effect. Anan-
single RCT of escitalopram, 10 mg once daily, but with no damide is also an agonist at TRPV1. Thus, endocannabinoids
benefit over placebo.133 TCAs, however, were more effica- have both pronociceptive and antinociceptive effects,
cious than placebo for abdominal pain in IBS in a meta- depending on the receptor.140 Interestingly, commensal
analysis of 4 RCTs132 and more recently in a 6-month trial bacteria can produce endocannabinoid-like molecules,141
in 463 patients.134 In one 12-week trial in refractory FD, although whether a microbial source of endocannabinoid-
imipramine led to a significant reduction in epigastric pain like molecules plays a role in visceral hypersensitivity is
scores vs placebo,135 but another trial of amitriptyline unknown.
demonstrated no benefit.133 The SNRI venlafaxine was In animal models of stress-induced visceral hypersensi-
assessed in a single 12-week RCT in IBS; abdominal pain tivity and in postinflammatory models, CB1 and CB2
 988 Ford et al Gastroenterology Vol. 166, Iss. 6
AND PERSPECTIVES
REVIEWS

Figure 4. Areas for future investigation in peripheral mechanisms of visceral pain. There is a need to identify peripheral
mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs host
sources of peripheral targets (eg, GABA, endocannabinoids, 5HT), is one such mechanistic area. Evaluation of the relative
contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combi-
nation therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet
effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of
peripherally restricted agents or subthreshold combinations of opiates, and CB1 receptor agonists. Because chronic visceral
pain is more common in women, future studies should evaluate whether pain mechanisms are sex-specific and whether
treatments should be used in a sex-specific manner. \, female; _, male.

agonists decrease the visceromotor response to colorectal study, although CB2 expression is increased in female pa-
distention.140,142–144 Endocannabinoids can either exert tients with IBS.146 These data suggest CB2 receptors on
their antinociceptive actions directly via CB1 and CB2 re- visceral afferents are sensitized by inflammation and, in
ceptors expressed on nociceptors142,145 or indirectly via turn, play a regulatory anti-nociceptive role.
down-regulation of mast cell or macrophage activation.140 Clinical trials. In a 12-week phase II dose-ranging
However, clinical use of cannabinoids is hampered by psy- study of olorinab in IBS, the proportion of patients experi-
chotropic adverse effects. Accordingly, there has been in- encing improvement in abdominal pain was not significantly
terest in synthesizing peripherally restricted cannabinoid higher with any dose studied.147 However, in those with
receptor agonists.142–144 moderate to severe pain at baseline, abdominal pain scores
A recent preclinical study of the peripherally restricted were significantly improved with 50 mg 3 times daily. No
CB2 receptor agonist, olorinab, was performed in rodent placebo-controlled trials of this drug in IBD have been
models of acute colitis and postinflammatory visceral conducted, although an 8-week open-label randomized
pain.142 Olorinab reversed the colitis-induced hypersensi- study recruiting patients with Crohn’s disease who reported
tivity to colorectal distention in both the acute and post- abdominal pain found a significant reduction in pain scores
inflammatory state; no effects on visceral pain were seen from baseline with olorinab.148 There is no evidence for
when olorinab was given to controls. Olorinab was able to other drugs acting on cannabinoid receptors for treating
decrease mechanosensitivity of ex vivo afferent nerves in a abdominal pain in gastrointestinal disorders.149
dose-dependent manner, both in acute colitis and in the
postinflammatory state, although CB2 expression was not g-Aminobutyric Acid and Visceral Pain
up-regulated in afferent nerves compared with controls.142 Pharmacology and preclinical studies. Functional
Unfortunately, only male mice were evaluated in this GABA receptors have been identified in the nerve terminals
June 2024 Mechanisms of Visceral Pain and Treatment 989

of colonic afferents. The activation of GABA receptors concepts, challenges, and compromises. Pain 2020;

AND PERSPECTIVES
(GABAA and GABAB) by endogenous GABA decreases 161:1976–1982.

REVIEWS
sensitivity of colonic afferents, whereas GABAA activation 2. Sinopoulou V, Gordon M, Dovey TM, et al. Interventions
also reduces visceral pain perception.150 Functional for the management of abdominal pain in ulcerative
GABAergic transmission has also been found in nociceptors, colitis. Cochrane Database Syst Rev 2021;7:CD013589.
producing strong analgesic effects.151 In addition to 3. Drossman DA. Functional gastrointestinal disorders:
endogenous production, certain bacteria expressing gluta- history, pathophysiology, clinical features and Rome IV.
mate decarboxylase, can produce GABA from glutamate.67 In Gastroenterology 2016;150:P1262–P1279.e2.
rodent models, GABA-producing bacteria have an analgesic 4. Takahashi K, Khwaja IG, Schreyer JR, et al. Post-
effect in stress-induced152 and fecal-retention153 models of inflammatory abdominal pain in patients with inflamma-
visceral hypersensitivity. tory bowel disease during remission: a comprehensive
Clinical trials. There has been 1 RCT of pregabalin in review. Crohns Colitis 360 2021;3:otab073.
both FD and IBS, but no trials in other painful gastrointes- 5. Hurtado-Lorenzo A, Honig G, Weaver SA, et al. Chronic
tinal disorders and no trials of gabapentin. Abdominal pain abdominal pain in IBD research initiative: unraveling
scores were significantly lower in patients assigned to biological mechanisms and patient heterogeneity to
titrated pregabalin vs placebo in a 12-week trial in IBS.154 personalize treatment and improve clinical outcomes.
Similarly, pregabalin, 75 mg daily, was superior to placebo Crohns Colitis 360 2021;3:otab034.
for epigastric pain scores in an 8-week trial in FD.155 6. Sperber AD, Bangdiwala SI, Drossman DA, et al.
Worldwide prevalence and burden of functional gastro-
intestinal disorders, results of Rome Foundation Global
Study. Gastroenterology 2021;160:99–114.e3.
Conclusions 7. Knowles CH, Aziz Q. Basic and clinical aspects of
Chronic visceral pain represents a substantial burden
gastrointestinal pain. Pain 2009;141:191–209.
to patients. Despite the potential for the evidence-based
8. Gracie DJ, Hamlin JP, Ford AC. Longitudinal impact of
treatments described above, a need remains for the
IBS-type symptoms on disease activity, healthcare uti-
development of novel therapeutics to treat sensitization of lization, psychological health, and quality of life in in-
peripheral pain pathways effectively. Future directions flammatory bowel disease. Am J Gastroenterol 2018;
should include the identification of microbial vs host 113:702–712.
sources of peripheral targets (eg, GABA, endocannabi- 9. Polster AV, Palsson OS, Tornblom H, et al. Subgroups
noids, 5HT), similar to current work evaluating histamine of IBS patients are characterized by specific, repro-
(Figure 4). ducible profiles of GI and non-GI symptoms and report
With respect to the microbiome, research should avoid differences in healthcare utilization: a population-
observational-based community profiling and focus on based study. Neurogastroenterol Motil 2019;31:
mechanistic approaches evaluating how microbiota or mi- e13483.
crobial products, or both, interact with nociceptors. Methods 10. Ma C, Congly SE, Novak KL, et al. Epidemiologic burden
to test the relative contribution of each pathophysiologic and treatment of chronic symptomatic functional bowel
mechanism to the sensitization of peripheral nociceptors disorders in the United States: a nationwide analysis.
and their role in overlapping pain syndromes in individual Gastroenterology 2021;160:88–98.e4.
patients is also required. This would allow the use of spe- 11. Chhibba T, Guizzetti L, Seow CH, et al. Frequency of
cific drug combinations to target multiple mechanisms opioid prescription at emergency department discharge
synergistically. in patients with inflammatory bowel disease: a nation-
Given the sex bias of chronic visceral pain, future studies wide analysis. Clin Gastroenterol Hepatol 2021;
should evaluate whether pain mechanisms are sex-specific 19:2064–2071.e1.
or whether treatments should be used in a sex-specific 12. LeBrett WG, Chang L. Prescription pain medications for
manner. Identifying whether differing or similar peripheral disorders of gut-brain interaction: comparing usage
mechanisms are involved in the development of chronic patterns with clinical practice recommendations. Neu-
visceral pain in patients with IBD vs painful DGBI will be rogastroenterol Motil 2023;35:e14645.
important. Finally, evaluation of the relative contribution of 13. Shin A, Kashyap PC. Multi-omics for biomarker ap-
peripheral vs central sensitization to symptoms would be proaches in the diagnostic evaluation and management
important to individualize patient therapy. Continued of abdominal pain and irritable bowel syndrome: what
multidisciplinary collaboration between clinician-scientists lies ahead. Gut Microbes 2023;15:2195792.
and bench-based scientists with the use of innovative 14. Aguilera-Lizarraga J, Florens MV, Viola MF, et al. Local
reverse translational approaches is necessary to advance immune response to food antigens drives meal-induced
this field, identify new target pathways, and improve the abdominal pain. Nature 2021;590:151–156.
clinical management of patients. 15. Aguilera-Lizarraga J, Hussein H, Boeckxstaens GE. Im-
mune activation in irritable bowel syndrome: what is the
evidence? Nat Rev Immunol 2022;22:674–686.
References 16. Brookes SJ, Spencer NJ, Costa M, et al. Extrinsic pri-
1. Raja SN, Carr DB, Cohen M, et al. The revised Interna- mary afferent signalling in the gut. Nat Rev Gastroenterol
tional Association for the Study of Pain definition of pain: Hepatol 2013;10:286–296.
 990 Ford et al Gastroenterology Vol. 166, Iss. 6

17. Hockley JRF, Taylor TS, Callejo G, et al. Single-cell 34. Castro J, Harrington AM, Hughes PA, et al. Linaclotide
AND PERSPECTIVES

RNAseq reveals seven classes of colonic sensory inhibits colonic nociceptors and relieves abdominal pain
REVIEWS

neuron. Gut 2019;68:633–644. via guanylate cyclase-C and extracellular cyclic guano-
18. Vermeulen W, De Man JG, Pelckmans PA, et al. sine 30 ,50 -monophosphate. Gastroenterology 2013;
Neuroanatomy of lower gastrointestinal pain disorders. 145:1334–1346.e1–11.
World J Gastroenterol 2014;20:1005–1020. 35. Silos-Santiago I, Hannig G, Eutamene H, et al. Gastro-
19. Gold MS, Gebhart GF. Nociceptor sensitization in pain intestinal pain: unraveling a novel endogenous pathway
pathogenesis. Nat Med 2010;16:1248–1257. through uroguanylin/guanylate cyclase-C/cGMP activa-
20. Brumovsky PR, Gebhart GF. Visceral organ cross- tion. Pain 2013;154:1820–1830.
sensitization—an integrated perspective. Auton Neuro- 36. Barton JR, Londregran AK, Alexander TD, et al. Intestinal
sci 2010;153:106–115. neuropod cell GUCY2C regulates visceral pain. J Clin
21. Feng B, Guo T. Visceral pain from colon and rectum: the Invest 2023;133:e165578.
mechanotransduction and biomechanics. J Neural 37. Black CJ, Burr NE, Quigley EMM, et al. Efficacy of se-
Transm (Vienna) 2020;127:415–429. cretagogues in patients with irritable bowel syndrome
22. Xie Z, Feng J, Hibberd TJ, et al. Piez02 channels with constipation: systematic review and network meta-
expressed by colon-innervating TRPV1-lineage neurons analysis. Gastroenterology 2018;155:1753–1763.
mediate visceral mechanical hypersensitivity. Neuron 38. Chey WD, Sayuk GS, Bartolini W, et al. Randomized trial
2023;111:526–538.e4. of 2 delayed–release formulations of linaclotide in pa-
23. Vanner S, Greenwood-Van Meerveld B, Mawe G, et al. tients with irritable bowel syndrome with constipation.
Fundamentals of neurogastroenterology: basic science. Am J Gastroenterol 2021;116:354–361.
Gastroenterology 2016;150:P1280–P1291. 39. Sternini C, Patierno S, Selmer IS, et al. The opioid sys-
24. Hanning N, Edwinson AL, Ceuleers H, et al. Intestinal tem in the gastrointestinal tract. Neurogastroenterol
barrier dysfunction in irritable bowel syndrome: a sys- Motil 2004;16(Suppl 2):3–16.
tematic review. Therap Adv Gastroenterol 2021;14: 40. Jimenez-Vargas NN, Gong J, Wisdom MJ, et al. Endo-
1756284821993586. somal signaling of delta opioid receptors is an endoge-
25. Vivinus-Nebot M, Frin-Mathy G, Bzioueche H, et al. nous mechanism and therapeutic target for relief from
Functional bowel symptoms in quiescent inflammatory inflammatory pain. Proc Natl Acad Sci U S A 2020;
bowel diseases: role of epithelial barrier disruption and 117:15281–15292.
low-grade inflammation. Gut 2014;63:744–752. 41. Philippe D, Chakass D, Thuru X, et al. Mu opioid receptor
26. Bayrer JR, Castro J, Venkataraman A, et al. Gut expression is increased in inflammatory bowel diseases:
enterochromaffin cells drive visceral pain and anxiety. implications for homeostatic intestinal inflammation. Gut
Nature 2023;616:137–142. 2006;55:815–823.
27. Waldman SA, Camilleri M. Guanylate cyclase-C as a 42. Stein C. Opioid analgesia: recent developments. Curr
therapeutic target in gastrointestinal disorders. Gut Opin Support Palliat Care 2020;14:112–117.
2018;67:1543–1552. 43. Koponen ME, Forget P. Pharmacological interventions
28. Müller T, Rasool I, Heinz-Erian P, et al. Congenital for opioid-induced hyperalgesia: a scoping review of
secretory diarrhoea caused by activating germline mu- preclinical trials. J Clin Med 2022;11:7060.
tations in GUCY2C. Gut 2016;65:1306–1313. 44. Stein C. New concepts in opioid analgesia. Expert Opin
29. Tronstad RR, Kummen M, Holm K, et al. Guanylate Investig Drugs 2018;27:765–775.
cyclase C activation shapes the intestinal microbiota in 45. Fürst S, Zádori ZS, Zádor F, et al. On the role of pe-
patients with familial diarrhea and increased suscepti- ripheral sensory and gut mu opioid receptors: peripheral
bility for Crohn’s disease. Inflamm Bowel Dis 2017; analgesia and tolerance. Molecules 2020;25:2473.
23:1752–1761. 46. Kumar R. Loperamide: from antidiarrheal to analgesic.
30. Brenna O, Bruland T, Furnes MW, et al. The guanylate J Opioid Manag 2013;9:301–302.
cyclase-C signaling pathway is down-regulated in in- 47. Li X, Li B, Zhang J, et al. Efficacy of opioid receptor
flammatory bowel disease. Scand J Gastroenterol 2015; modulators in patients with irritable bowel syndrome: a
50:1241–1252. systematic review and meta-analysis. Medicine (Balti-
31. Camilleri M, Carlson P, Acosta A, et al. RNA sequencing more) 2021;100:e24361.
shows transcriptomic changes in rectosigmoid mucosa 48. Fujita W, Gomes I, Dove LS, et al. Molecular character-
in patients with irritable bowel syndrome-diarrhea: a pilot ization of eluxadoline as a potential ligand targeting mu-
case-control study. Am J Physiol Gastrointest Liver delta opioid receptor heteromers. Biochem Pharmacol
Physiol 2014;306:G1089–G1098. 2014;92:448–456.
32. Waldman SA, Tenenbaum R, Foehl HC, et al. Blunted 49. Holzer P. Opioid receptors in the gastrointestinal tract.
evoked prouroguanylin endocrine secretion in chronic Regul Pept 2009;155:11–17.
constipation. Clin Transl Gastroenterol 2019;10: 50. Jimenez-Vargas NN, Yu Y, Jensen DD, et al. Agonist that
e00016. activates the micro-opioid receptor in acidified micro-
33. Eutamene H, Bradesi S, Larauche M, et al. Guanylate environments inhibits colitis pain without side effects.
cyclase C-mediated antinociceptive effects of linaclotide Gut 2022;71:695–704.
in rodent models of visceral pain. Neurogastroenterol 51. Yu Y, Tsang QK, Jaramillo-Polanco J, et al. Cannabinoid
Motil 2010;22:312-e84. 1 and mu-opioid receptor agonists synergistically inhibit
June 2024 Mechanisms of Visceral Pain and Treatment 991

abdominal pain and lack side effects in mice. J Neurosci 68. Bellono NW, Bayrer JR, Leitch DB, et al. Enterochro-

AND PERSPECTIVES
2022;42:6313–6324. maffin cells are gut chemosensors that couple to sen-

REVIEWS
52. Gottesman-Katz L, Latorre R, Vanner S, et al. Targeting sory neural pathways. Cell 2017;170:185–198.e16.
G protein-coupled receptors for the treatment of chronic 69. Reigstad CS, Salmonson CE, Rainey JF 3rd, et al. Gut
pain in the digestive system. Gut 2021;70:970–981. microbes promote colonic serotonin production through
53. Ji Y, Murphy AZ, Traub RJ. Estrogen modulation of an effect of short-chain fatty acids on enterochromaffin
morphine analgesia of visceral pain in female rats is cells. FASEB J 2015;29:1395–1403.
supraspinally and peripherally mediated. J Pain 2007; 70. Qi J, Buzas K, Fan H, et al. Painful pathways induced by
8:494–502. TLR stimulation of dorsal root ganglion neurons.
54. Lavo B, Stenstam M, Nielsen AL. Loperamide in treat- J Immunol 2011;186:6417–6426.
ment of irritable bowel syndrome—a double-blind pla- 71. Chiu IM, Heesters BA, Ghasemlou N, et al. Bacteria
cebo controlled study. Scand J Gastroenterol 1987; activate sensory neurons that modulate pain and
130:77–80. inflammation. Nature 2013;501:52–57.
55. Hovdenak N. Loperamide treatment of the irritable bowel 72. Banasiewicz T, Krokowicz L, Stojcev Z, et al. Micro-
syndrome. Scand J Gastroenterol 1987;130:81–84. encapsulated sodium butyrate reduces the frequency of
56. Black CJ, Burr NE, Camilleri M, et al. Efficacy of phar- abdominal pain in patients with irritable bowel syndrome.
macological therapies in patients with IBS with diarrhoea Colorectal Dis 2013;15:204–209.
or mixed stool pattern: systematic review and network 73. Ruiz-Medina J, Flores JA, Tasset I, et al. Alteration of
meta-analysis. Gut 2020;69:74–82. neuropathic and visceral pain in female C57BL/6J mice
57. Crouzet L, Gaultier E, Del’Homme C, et al. The hyper- lacking the PPAR-alpha gene. Psychopharmacology
sensitivity to colonic distension of IBS patients can be (Berl) 2012;222:477–488.
transferred to rats through their fecal microbiota. Neu- 74. LoVerme J, Russo R, La Rana G, et al. Rapid broad-
rogastroenterol Motil 2013;25:e272–e282. spectrum analgesia through activation of peroxisome
58. McVey Neufeld KA, Mao YK, Bienenstock J, et al. The proliferator-activated receptor-alpha. J Pharmacol Exp
microbiome is essential for normal gut intrinsic primary Ther 2006;319:1051–1061.
afferent neuron excitability in the mouse. Neuro- 75. Kelly CJ, Zheng L, Campbell EL, et al. Crosstalk between
gastroenterol Motil 2013;25:183-e88. microbiota-derived short-chain fatty acids and intestinal
59. O’Mahony SM, Felice VD, Nally K, et al. Disturbance of epithelial HIF augments tissue barrier function. Cell Host
the gut microbiota in early-life selectively affects visceral Microbe 2015;17:662–671.
pain in adulthood without impacting cognitive or anxiety- 76. Vinolo MA, Rodrigues HG, Nachbar RT, et al. Regulation
related behaviors in male rats. Neuroscience 2014; of inflammation by short chain fatty acids. Nutrients
277:885–901. 2011;3:858–876.
60. Kannampalli P, Pochiraju S, Chichlowski M, et al. Pro- 77. Han Q, Fang J, Li J. Kynurenine aminotransferase and
biotic Lactobacillus rhamnosus GG (LGG) and prebiotic glutamine transaminase K of Escherichia coli: identity
prevent neonatal inflammation-induced visceral hyper- with aspartate aminotransferase. Biochem J 2001;
sensitivity in adult rats. Neurogastroenterol Motil 2014; 360:617–623.
26:1694–1704. 78. Keszthelyi D, Troost FJ, Masclee AA. Understanding the
61. Miquel S, Martin R, Lashermes A, et al. Anti-nociceptive role of tryptophan and serotonin metabolism in gastro-
effect of Faecalibacterium prausnitzii in non- intestinal function. Neurogastroenterol Motil 2009;
inflammatory IBS-like models. Sci Rep 2016;6:19399. 21:1239–1249.
62. Aguilera M, Cerda-Cuellar M, Martinez V. Antibiotic- 79. Zelante T, Iannitti RG, Cunha C, et al. Tryptophan ca-
induced dysbiosis alters host-bacterial interactions and tabolites from microbiota engage aryl hydrocarbon re-
leads to colonic sensory and motor changes in mice. Gut ceptor and balance mucosal reactivity via interleukin-22.
Microbes 2015;6:10–23. Immunity 2013;39:372–385.
63. Tramullas M, Collins JM, Fitzgerald P, et al. Estrous 80. Wang J, Simonavicius N, Wu X, et al. Kynurenic acid as a
cycle and ovariectomy-induced changes in visceral pain ligand for orphan G protein-coupled receptor GPR35.
are microbiota-dependent. iScience 2021;24:102850. J Biol Chem 2006;281:22021–22028.
64. Jeffery IB, O’Toole PW, Ohman L, et al. An irritable bowel 81. Edwinson AL, Yang L, Peters S, et al. Gut microbial beta-
syndrome subtype defined by species-specific alter- glucuronidases regulate host luminal proteases and are
ations in faecal microbiota. Gut 2012;61:997–1006. depleted in irritable bowel syndrome. Nat Microbiol
65. Rajilic-Stojanovic M, Biagi E, Heilig HG, et al. Global and 2022;7:680–694.
deep molecular analysis of microbiota signatures in fecal 82. Cenac N, Andrews CN, Holzhausen M, et al. Role for
samples from patients with irritable bowel syndrome. protease activity in visceral pain in irritable bowel syn-
Gastroenterology 2011;141:1792–1801. drome. J Clin Invest 2007;117:636–647.
66. Saffouri GB, Shields-Cutler RR, Chen J, et al. Small in- 83. Steck N, Mueller K, Schemann M, et al. Bacterial pro-
testinal microbial dysbiosis underlies symptoms asso- teases in IBD and IBS. Gut 2012;61:1610–1618.
ciated with functional gastrointestinal disorders. Nat 84. Desai MS, Seekatz AM, Koropatkin NM, et al. A dietary
Commun 2019;10:2012. fiber–deprived gut microbiota degrades the colonic
67. Strandwitz P. Neurotransmitter modulation by the gut mucus barrier and enhances pathogen susceptibility.
microbiota. Brain Res 2018;1693:128–133. Cell 2016;167:1339–1353.e21.
 992 Ford et al Gastroenterology Vol. 166, Iss. 6

85. Singh P, Grabauskas G, Zhou SY, et al. High FODMAP 101. Thangam EB, Jemima EA, Singh H, et al. The role of
AND PERSPECTIVES

diet causes barrier loss via lipopolysaccharide-mediated histamine and histamine receptors in mast cell-mediated
REVIEWS

mast cell activation. JCI Insight 2021;6:e146529. allergy and inflammation: the hunt for new therapeutic
86. Vernia P, Marcheggiano A, Caprilli R, et al. Short-chain targets. Front Immunol 2018;9:1873.
fatty acid topical treatment in distal ulcerative colitis. 102. Dy M, Schneider E. Histamine-cytokine connection in
Aliment Pharmacol Ther 1995;9:309–313. immunity and hematopoiesis. Cytokine Growth Factor
87. Steinhart AH, Hiruki T, Brzezinski A, et al. Treatment of left- Rev 2004;15:393–410.
sided ulcerative colitis with butyrate enemas: a controlled 103. Lieberman P. The basics of histamine biology. Ann Al-
trial. Aliment Pharmacol Ther 1996;10:729–736. lergy Asthma Immunol 2011;106(Suppl):S2–S5.
88. Breuer RI, Soergel KH, Lashner BA, et al. Short chain fatty 104. Deiteren A, De Man JG, Pelckmans PA, et al. Histamine
acid rectal irrigation for left-sided ulcerative colitis: a rand- H(4) receptors in the gastrointestinal tract. Br J Phar-
omised, placebo controlled trial. Gut 1997;40:485–491. macol 2015;172:1165–1178.
89. Prior A, Whorwell P. Double blind study of ispaghula in 105. Barbara G, Feinle-Bisset C, Ghoshal UC, et al. The in-
irritable bowel syndrome. Gut 1987;28:1510–1513. testinal microenvironment and functional gastrointestinal
90. Bijkerk CJ, de Wit NJ, Muris JW, et al. Soluble or insol- disorders. Gastroenterology 2016;150:1305–1318.e8.
uble fibre in irritable bowel syndrome in primary care? 106. Shah A, Fairlie T, Brown G, et al. Duodenal eosinophils
Randomised placebo controlled trial. BMJ 2009; and mast cells in functional dyspepsia: a systematic
339:b3154. review and meta-analysis of case-control studies. Clin
91. Black CJ, Staudacher HM, Ford AC. Efficacy of a low Gastroenterol Hepatol 2022;20:2229–2242.e29.
FODMAP diet in irritable bowel syndrome: systematic 107. Lopez Lopez C, Jaramillo Polanco J, Tsang QK, et al.
review and network meta-analysis. Gut 2022; A283: Role of immunoglobulin E in abdominal pain due
71:1117–1126. to interactions between diet and stress in a model of IBS
92. Cox SR, Lindsay JO, Fromentin S, et al. Effects of low (abstract). J Can Assoc Gastro 2023;6(Suppl 1):94–95.
FODMAP diet on symptoms, fecal microbiome, and 108. De Palma G, Shimbori C, Reed DE, et al. Histamine
markers of inflammation in patients with quiescent in- production by the gut microbiota induces visceral
flammatory bowel disease in a randomized trial. hyperalgesia through histamine 4 receptor signaling in
Gastroenterology 2020;158:176–188.e7. mice. Sci Transl Med 2022;14:eabj1895.
93. Pedersen N, Ankersen DV, Felding M, et al. Low-FOD- 109. Klooker TK, Braak B, Koopman KE, et al. The mast cell
MAP diet reduces irritable bowel symptoms in patients stabiliser ketotifen decreases visceral hypersensitivity
with inflammatory bowel disease. World J Gastroenterol and improves intestinal symptoms in patients with irri-
2017;23:3356–3366. table bowel syndrome. Gut 2010;59:1213–1221.
94. Imdad A, Pandit NG, Zaman M, et al. Fecal trans- 110. Wouters MM, Balemans D, Van Wanrooy S, et al. His-
plantation for treatment of inflammatory bowel disease. tamine receptor H1-mediated sensitization of TRPV1
Cochrane Database Syst Rev 2023;4:CD012774. mediates visceral hypersensitivity and symptoms in pa-
95. Ianiro G, Eusebi LH, Black CJ, et al. Systematic review tients with irritable bowel syndrome. Gastroenterology
with meta-analysis: efficacy of faecal microbiota trans- 2016;150:875–887.e9.
plantation for the treatment of irritable bowel syndrome. 111. Decraecker L, De Looze D, Hirsch D, et al. Treatment
Aliment Pharmacol Ther 2019;50:240–248. with the histamine 1 receptor antagonist ebastine for
96. Holvoet T, Joossens M, Vázquez-Castellanos JF, et al. non-constipated irritable bowel syndrome: a double-
Fecal microbiota transplantation reduces symptoms in blind randomized placebo-controlled trial. Neuro-
some patients with irritable bowel syndrome with pre- gastroenterol Motil 2023;35(Suppl 2):51.
dominant abdominal bloating: short- and long-term re- 112. Lobo B, Ramos L, Martínez C, et al. Downregulation of
sults from a placebo-controlled randomized trial. mucosal mast cell activation and immune response in
Gastroenterology 2021;160:145–157.e8. diarrhoea-irritable bowel syndrome by oral disodium
97. El-Salhy M, Hatlebakk JG, Gilja OH, et al. Efficacy of cromoglycate: a pilot study. United European Gastro-
faecal microbiota transplantation for patients with irrita- enterol J 2017;5:887–897.
ble bowel syndrome in a randomised, double-blind, 113. Balemans D, Boeckxstaens GE, Talavera K, et al. Tran-
placebo-controlled study. Gut 2020;69:859–867. sient receptor potential ion channel function in sensory
98. Fang H, Fu L, Li X, et al. Long-term efficacy and safety of transduction and cellular signaling cascades underlying
monotherapy with a single fresh fecal microbiota trans- visceral hypersensitivity. Am J Physiol Gastrointest Liver
plant for recurrent active ulcerative colitis: a prospective Physiol 2017;312:G635–G648.
randomized pilot study. Microb Cell Fact 2021;20:18. 114. Cho T, Chaban VV. Expression of P2X3 and TRPV1 re-
99. Trifan A, Burta O, Tiuca N, et al. Efficacy and safety of ceptors in primary sensory neurons from estrogen
gelsectan for diarrhoea-predominant irritable bowel receptors-alpha and estrogen receptor-beta knockout
syndrome: a randomised, crossover clinical trial. United mice. Neuroreport 2012;23:530–534.
European Gastroenterol J 2019;7:1093–1101. 115. van Wanrooij SJ, Wouters MM, Van Oudenhove L, et al.
100. Goodoory VC, Khasawneh M, Black CJ, et al. Efficacy of Sensitivity testing in irritable bowel syndrome with rectal
probiotics in irritable bowel syndrome: systematic review capsaicin stimulations: role of TRPV1 upregulation and
and meta-analysis. Gastroenterology 2023; sensitization in visceral hypersensitivity? Am J Gastro-
165:1206–1218. enterol 2014;109:99–109.
June 2024 Mechanisms of Visceral Pain and Treatment 993

116. Akbar A, Yiangou Y, Facer P, et al. Expression of the TRPV1 132. Black CJ, Yuan Y, Selinger CP, et al. Efficacy of soluble

AND PERSPECTIVES
receptor differs in quiescent inflammatory bowel disease fibre, antispasmodic drugs, and gut-brain neuro-

REVIEWS
with or without abdominal pain. Gut 2010;59:767–774. modulators in irritable bowel syndrome: a systematic
117. Lapointe TK, Basso L, Iftinca MC, et al. TRPV1 sensiti- review and network meta-analysis. Lancet Gastroenterol
zation mediates postinflammatory visceral pain following Hepatol 2020;5:117–131.
acute colitis. Am J Physiol Gastrointest Liver Physiol 133. Talley NJ, Locke GR, Saito YA, et al. Effect of amitrip-
2015;309:G87–G99. tyline and escitalopram on functional dyspepsia: a multi-
118. Esquerre N, Basso L, Defaye M, et al. Colitis-induced center, randomized, controlled study. Gastroenterology
microbial perturbation promotes postinflammatory 2015;149:340–349.
visceral hypersensitivity. Cell Mol Gastroenterol Hepatol 134. Ford AC, Wright-Hughes A, Alderson SL, et al. Amitrip-
2020;10:225–244. tyline at Low-Dose and Titrated for Irritable Bowel Syn-
119. Ingrosso MR, Ianiro G, Nee J, et al. Systematic review drome as Second-Line Treatment in primary care
and meta-analysis: efficacy of peppermint oil in irritable (ATLANTIS): a randomised, double-blind, placebo-
bowel syndrome. Aliment Pharmacol Ther 2022; controlled, phase 3 trial. Lancet 2023;402:1773–1785.
56:932–941. 135. Cheong PK, Ford AC, Cheung CKY, et al. Low-dose
120. Bortolotti M, Porta S. Effect of red pepper on symptoms imipramine for refractory functional dyspepsia: a rando-
of irritable bowel syndrome: preliminary study. Dig Dis mised, double-blind, placebo-controlled trial. Lancet
Sci 2011;56:3288–3295. Gastroenterol Hepatol 2018;3:837–844.
121. Bortolotti M, Coccia G, Grossi G, et al. The treatment of 136. Sharbafchi MR, Afshar H, Adhamian P, et al. Effects of
functional dyspepsia with red pepper. Aliment Pharma- venlafaxine on gastrointestinal symptoms, depression,
col Ther 2002;16:1075–1082. anxiety, stress, and quality of life in patients with the
122. Mawe GM, Hoffman JM. Serotonin signalling in the moderate-to-severe irritable bowel syndrome. J Res
gut—functions, dysfunctions and therapeutic targets. Med SciVolume 2020;25:115.
Nat Rev Gastroenterol Hepatol 2013;10:473–486. 137. van Kerkhoven LA, Laheij RJ, Aparicio N, et al. Effect of
123. Camilleri M. Genetics of human gastrointestinal sensa- the antidepressant venlafaxine in functional dyspepsia: a
tion. Neurogastroenterol Motil 2013;25:458–466. randomized, double-blind, placebo-controlled trial. Clin
124. Nasser Y, Boeckxstaens GE, Wouters MM, et al. Using Gastroenterol Hepatol 2008;6:746–752.
human intestinal biopsies to study the pathogenesis of 138. Adejumo AC, Ajayi TO, Adegbala OM, et al. Higher odds
irritable bowel syndrome. Neurogastroenterol Motil of irritable bowel syndrome among hospitalized patients
2014;26:455–469. using cannabis: a propensity-matched analysis. Eur J
125. Kaelberer MM, Buchanan KL, Klein ME, et al. A gut-brain Gastroenterol Hepatol 2019;31:756–765.
neural circuit for nutrient sensory transduction. Science 139. Ravikoff Allegretti J, Courtwright A, Lucci M, et al. Marijuana
2018;361:eaat5236. use patterns among patients with inflammatory bowel
126. Alcaino C, Knutson KR, Treichel AJ, et al. A population of disease. Inflamm Bowel Dis 2013;19:2809–2814.
gut epithelial enterochromaffin cells is mechanosensitive 140. Brierley SM, Greenwood-Van Meerveld B, Sarnelli G,
and requires Piez02 to convert force into serotonin et al. Targeting the endocannabinoid system for the
release. Proc Natl Acad Sci U S A 2018; treatment of abdominal pain in irritable bowel syndrome.
115:E7632–E7641. Nat Rev Gastroenterol Hepatol 2023;20:5–25.
127. Gunn D, Topan R, Barnard L, et al. Randomised, 141. Cohen LJ, Esterhazy D, Kim SH, et al. Commensal
placebo-controlled trial and meta-analysis show benefit bacteria make GPCR ligands that mimic human signal-
of ondansetron for irritable bowel syndrome with diar- ling molecules. Nature 2017;549:48–53.
rhoea: the TRITON trial. Aliment Pharmacol Ther 2023; 142. Castro J, Garcia-Caraballo S, Maddern J, et al. Olorinab
57:1258–1271. (APD371), a peripherally acting, highly selective, full
128. Shah ED, Lacy BE, Chey WD, et al. Tegaserod for irri- agonist of the cannabinoid receptor 2, reduces colitis-
table bowel syndrome with constipation in women induced acute and chronic visceral hypersensitivity in
younger than 65 years without cardiovascular disease: rodents. Pain 2022;163:e72–e86.
pooled analyses of 4 controlled trials. Am J Gastro- 143. Shen L, Yang XJ, Qian W, et al. The role of peripheral
enterol 2021;116:1601–1611. cannabinoid receptors type 1 in rats with visceral hy-
129. Vakil N, Laine L, Talley NJ, et al. Tegaserod treatment for persensitivity induced by chronic restraint stress.
dysmotility-like functional dyspepsia: results of two J Neurogastroenterol Motil 2010;16:281–290.
randomized, controlled trials. Am J Gastroenterol 2008; 144. Iwata Y, Ando K, Taniguchi K, et al. Identification of a
103:1906–1919. highly potent and selective CB2 agonist, RQ-00202730,
130. Luthra P, Camilleri M, Burr NE, et al. Efficacy of drugs in for the treatment of irritable bowel syndrome. Bioorg
chronic idiopathic constipation: a systematic review and Med Chem Lett 2015;25:236–240.
network meta-analysis. Lancet Gastroenterol Hepatol 145. Hillsley K, McCaul C, Aerssens J, et al. Activation of the
2019;4:831–844. cannabinoid 2 (CB2) receptor inhibits murine mesenteric
131. Drossman DA, Tack J, Ford AC, et al. Neuromodulators afferent nerve activity. Neurogastroenterol Motil 2007;
for functional gastrointestinal disorders (disorders of gut- 19:769–777.
brain interaction): a Rome Foundation working team 146. Dothel G, Chang L, Shih W, et al. micro-opioid receptor,
report. Gastroenterology 2018;154:1140–1171.e1. beta-endorphin, and cannabinoid receptor-2 are increased
 994 Ford et al Gastroenterology Vol. 166, Iss. 6

in the colonic mucosa of irritable bowel syndrome patients. sensitivity in the intestine. Neurogastroenterol Motil
AND PERSPECTIVES

Neurogastroenterol Motil 2019;31:e13688. 2017;29:e12904.

REVIEWS

147. Chang L, Cash BD, Lembo A, et al. Efficacy and safety of 154. Saito YA, Almazar AE, Tilkes KE, et al. Randomised
olorinab, a full agonist of the cannabinoid receptor 2, for clinical trial: pregabalin vs placebo for irritable bowel
the treatment of abdominal pain in patients with irritable syndrome. Aliment Pharmacol Ther 2019;49:389–397.
bowel syndrome: results from a phase 2b randomized 155. Kotikula I, Thinrungroj N, Pinyopornpanish K, et al.
placebo-controlled trial (CAPTIVATE). Neuro- Randomised clinical trial: the effects of pregabalin vs
gastroenterol Motil 2023;35:e14539. placebo on functional dyspepsia. Aliment Pharmacol
148. Yacyshyn BR, Hanauer S, Klassen P, et al. Safety, Ther 2021;54:1026–1032.
pharmacokinetics, and efficacy of olorinab, a peripher-
ally acting, highly selective, full agonist of the cannabi-
noid receptor 2, in a phase 2a study of patients with
Received August 25, 2023. Accepted January 5, 2024.
chronic abdominal pain associated with Crohn’s dis-
ease. Crohns Colitis 360 2021;3:otaa089. Correspondence
149. Bilbao A, Spanagel R. Medical cannabinoids: a Address correspondence to: Yasmin Nasser, MD, PhD, FRCPC, Division of
Gastroenterology and Hepatology, Department of Medicine, Health Sciences
pharmacology-based systematic review and meta-analysis 1667, 3330 Hospital Drive Northwest, Calgary, Alberta T2N4N1, Canada.
for all relevant medical indications. BMC Med 2022;20:259. e-mail: [email protected].
150. Loeza-Alcocer E, McPherson TP, Gold MS. Peripheral Conflicts of interest
GABA receptors regulate colonic afferent excitability and These authors disclose the following: Stephen Vanner is cofounder of pHarm
visceral nociception. J Physiol 2019;597:3425–3439. Therapeutics Inc, a company that is developing pH-sensitive analgesics that
selectively target sites of inflammation where pain originates. Purna C.
151. Du X, Hao H, Yang Y, et al. Local GABAergic signaling Kashyap is an ad hoc consultant for Pendulum Therapeutics and Intrinsic
within sensory ganglia controls peripheral nociceptive Medicine and holds the patent US20170042860A1 “Methods and materials
for using Ruminococcus gnavus or Clostridium sporogenes to treat
transmission. J Clin Invest 2017;127:1741–1756. gastrointestinal disorders” for use of tryptamine producing bacteria to treat
152. Laroute V, Beaufrand C, Gomes P, et al. Lactococcus gastrointestinal disorders. Mayo Clinic and Purna C. Kashyap have a
financial interest related to use of tryptamine-producing bacteria. The
lactis NCD02118 exerts visceral antinociceptive proper- remaining authors disclose no conflicts.
ties in rat via GABA production in the gastro-intestinal
tract. Elife 2022;11:e77100. Funding
Funded by the Canadian Institutes of Health Research (CIHR) (to Yasmin
153. Pokusaeva K, Johnson C, Luk B, et al. GABA- Nasser) and the National Institutes of Health, National Institute of Diabetes
producing Bifidobacterium dentium modulates visceral and Digestive and Kidney Diseases (DK114007) (to Purna C. Kashyap).