IBS Clinical Care Gaps and the Potential of Future Therapeutics based on Peripheral Visceral Afferent Modulation

Abstract

Current management of irritable bowel syndrome (IBS) is focused on bowel dysfunction or central neuromodulators. Aims of this review were to: appraise unmet needs in IBS treatment; review the physiology of visceral afferent functions and specifically receptors in the dorsal root ganglion (DRG) cell bodies of the first order neurones; and summarize evidence of efficacy of pharmacological approaches directed at receptors expressed by DRGs based on rodent models of visceral hypersensitivity and randomized, controlled trials in IBS. A literature search was done using terms identified in the aims section. The greatest need in IBS is safe treatment of pain. Physiological and noxious stimuli are conducted to the brain through vagal and pelvic parasympathetic pathways, and noxious stimuli through visceral afferents and spinal cord. Peripheral visceral afferents, with cell bodies in DRG, have receptors targeted pharmacologically to relieve pain (or surrogates) in rodent IBS models of visceral hypersensitivity. Advances in understanding mechanisms of visceral hypersensitivity lead to consideration of targeting receptors on the DRG. Those receptors on DRGs are also expressed in CNS and include α−2 adrenergic, somatostatin-SS2, 5-HT₃, cannabinoid, α4β2 and α6β2 nicotininc cholinergic, calcitonin gene-related peptide, κ-opioid and GLP-1 receptors and acid-gated ion channels. Evidence from predominantly pre-clinical and human studies supporting these peripheral targets is summarized, and provides the rationale to develop novel, peripherally-restricted pharmaceuticals to reduce visceral pain in IBS. Novel neuromodulators restricted to peripheral actions and targeting DRG receptors would constitute a novel alternative to central neuromodulators for IBS-pain, in addition to potential effects on colonic transit or secretion.

Introduction

Although biomarker-based approaches such as identification of pelvic floor dyssynergia or bile acid diarrhea enhance treatment of irritable bowel syndrome (IBS),¹ there is still need to optimize empirical choice of treatment of predominant symptoms. The mechanisms of action of drugs currently used in treatment of lower gut disorders of gut-brain interaction (DGBI) are documented elsewhere and briefly reviewed in Supplement. This narrative review addresses 3 questions in current and future management in IBS: Is there need for new medications for diarrhea-predominant IBS (IBS-D) or constipation-predominant IBS (IBS-C)? What is the greatest unmet need in IBS? Given relative paucity of peripherally-directed, safe treatment of IBS-related discomfort/pain, the third question is whether targeting peripheral mechanisms involved in visceral sensation and mediating pain in IBS is promising based on animal models of IBS and human trials in IBS. The review was based on a search of all published literature identified using PubMed in all languages up to October 2025; the search terms included the combination of IBS pain and peripheral analgesia, and specific classes of pharmacological agents: α2-adrenergic agonist, serotonergic 5-HT₃ antagonist, somatostatin type 2 agonist, mast cell stabilizer, histamine H₁ receptor antagonist, calcitonin gene related peptide (CGRP) antagonist, cannabinoid agents, and glucagon-like peptide-1 (GLP-1) agonist.

Is There Still Need for Medications for Treatment of IBS?

There are many FDA-approved medications that have statistically significant efficacy for the treatment of bowel dysfunction and global endpoints in IBS-C and IBS-D. The greatest unmet need is the management of IBS-associated pain. The inadequate efficacy of current treatment with gut-brain neuromodulators for IBS is evidenced by the relative risk (RR) of global IBS symptoms or abdominal pain not improving compared to placebo of 0·77 (95% CI 0·69–0·87) and 0·72 (95% CI 0·62–0·83) respectively.² Efficacy of behavioral, central, anti-microbial, and other approaches to treat IBS-related pain^3,4 as well as a critical appraisal of the evidence of efficacy of approaches such as centrally-acting antidepressants, probiotics, antispasmodics and muscle relaxants for IBS⁵ have been reviewed elsewhere.

Potential adverse effects such as drowsiness, dizziness, and ability to concentrate or mental performance associated with central neuromodulators also impact the dose used. In clinical trials, central neuromodulators were associated with significantly higher withdrawal rate because of adverse events compared with placebo, particularly with tricyclic antidepressants and alpha-2-delta ligand agents.² Significant effects with low dose amitriptyline (30mg or lower)⁶ are associated with modest (only ~5%) absolute difference in the IBS Severity Scoring System (IBS-SSS) score compared to placebo. Given black box warnings restricting use of alosetron to women, contraindication of eluxadoline with prior cholecystectomy as well as potential adverse effects (respectively ischemic colitis and spasm of the sphincter of Oddi that may lead to pancreatitis), a second unmet need is the control of diarrhea in IBS-D.

Therefore, the next sections discuss the neuroanatomy and measurement of visceral sensation, and mechanisms of action of peripherally-active agents for visceral pain and potentially for diarrhea associated with IBS.

Gut Sensation and Visceral Hypersensitivity

Gut sensation involves several important anatomical structures: in the mucosa, the enteroendocrine cells (EECs) respond to chemical and mechanical stimuli; in the lamina propria, intraganglionic laminar endings mediate mechano-transduction; the prevertebral ganglia, spinal cord, brainstem are involved in reflex responses; and a three-neuron chain connects visceral sensation to supraspinal perception as well as autonomic (e.g. cardiovascular) responses to the stimuli. The predominant mediators involved in visceral sensation are 5-HT, substance P, calcitonin gene-related peptide (CGRP), norepinephrine, κ-opiate, and others including GLP-1.

a. Neuroanatomy: Three neurons and dorsal root ganglia

The neuroanatomy of visceral sensation is summarized in Figure 1 and detailed in the Supplement. The cell bodies of the first order neuron are located in the dorsal root ganglion (DRG).

Figure 1.

Visceral afferent pathways from the gastrointestinal tract and potential receptor targets in dorsal root ganglia and dorsal horn neurons as well as descending pathways modulating the function of the dorsal horn neurons constitute the second order neurons conveying afferent signals up the spinal cord to brain centers (Created in BioRender. Camilleri, M. (2025) https://BioRender.com/ekb3zwo)

b. Method to appraise visceral sensation and compliance

A validated method⁷ to measure rectal or colonic sensation using an inflatable polyethylene balloon linked to barostat device that inflates air at selected, constant pressures has been extensively reviewed. This method measures gut compliance and sensation (Figure 2) during ramp inflation, 4mmHg steps maintained for 1 minute (0–60 mmHg). The volume responses to inflation pressures define the compliance of the viscus. Sensation thresholds for gas, first desire to defecate, urgency, and pain are indicated by the distention pressures at which those sensations are perceived. Sensory ratings for gas, urgency and pain (on 100mm visual analog scale) are assessed during random order, 60 second duration, phasic distentions at 12-, 24-, 30- and 36-mmHg above the baseline pressure that records respiration-induced variations in balloon volumes.

Figure 2.

Method to measure rectal compliance and sensation using an air-filled polyethylene balloon with pressures controlled with a barostat. The method assesses rectal compliance and pressure thresholds of sensations using stepwise increases in intraballoon pressure (ascending method of limits) as well as sensations of gas, urgency, and pain using a visual analog scale during random order phasic distentions at specified pressure levels above the baseline operating pressure, that is the pressure at which respiratory variation is detected in the air-inflated balloon. Created in BioRender. Camilleri, M. (2025) https://BioRender.com/ekb3zwo

c. Summary documenting rectal or colonic hypersensitivity or hyperalgesia in IBS

Rectal hypersensitivity in IBS has been documented as the onset of pain at lower volumes of distention of an intrarectal balloon, particularly in IBS-D compared to healthy controls.^8,9 In addition, among IBS patients with normal thresholds for rectal sensation, the patients may experience greater discomfort, suggesting hyperalgesia rather than hypersensitivity.¹⁰ Hyperalgesia was significantly associated with symptoms severity, not with demographics or psychological disturbances.¹¹

Visceral Sensation: Mechanisms

Physiological stimuli arising in visceral mechanoreceptors are transmitted to the central nervous system via vagal or sacral afferents, whereas noxious stimuli reach the central nervous system via spinal afferents.^12–14 Mechanical stimuli arising in the gut at the mucosal or muscular layers activate splanchnic and pelvic afferents whose cell bodies are in thoraco-lumbar and lumbosacral DRG, and harbor several receptors including TRPV1.¹⁵ DRG neurons are key in pain sensation and signal transmission to the CNS,^16,17 and key pain-signaling molecules have been identified using RNAscope in situ hybridization.^16,18–21 Human DRGs express abundant immunoreactivity for key pain transduction receptors, including the thermosensitive ion channels TRPV1, TRPV4 and TRPA1, mechanosensitive PIEZO1 and PIEZO2, and the nociceptive-specific Nav1.8. These receptors co-localized with calcitonin gene-related peptide (CGRP), a marker for peptidergic sensory neurons, as well as μ, δ and κ opioid receptors.²² Additionally, human DRGs express nociceptin/ orphanin-FQ opioid receptors and μ, δ and κ opioid receptors.²³ Targeting these primary afferent and DRG mechanisms constitutes a potential approach to develop effective, peripherally-active medications that are independent, or potentially devoid of actions targeting the CNS directly, as discussed below (Figure 1).

Mechanisms of Action of Agents that include Peripheral Effects on Visceral Pain and Evidence of Efficacy in IBS or Other Pain Syndromes

These mechanisms are summarized in Figure 1. A summary of effects of DRG modulators in visceral hypersensitivity and IBS is provided in Table 1. It is important to note that, when a medication also alters compliance, its effect on sensation is not exclusively on afferents, but rather, the reduced sensation may reflect increased distensibility which reduces activation of afferents arising in the muscle layers of the bowel. In addition, these different classes of medications also have effects on dorsal horn neurons in addition to effects on the DRG.

Table 1.

Summary of current state of DRG modulators in visceral hypersensitivity and IBS

Class/mechanism	Example; FDA approval	Effect on visceral afferent	Effect on compliance	Conclusion from Human studies in IBS (RCTs)
α2-adrenergic agonist	Clonidine approved	Reduced rectal sensation to distension only in IBS-C	Increased	Small mechanistic RCTs; dual effect hypotension; consider patch
5-HT3 antagonist	Alosetron approved for IBS-D; Ondansetron approved as antiemetic; Cilansetron not approved	Reduced colonic sensation to distension only in IBS-D	Increased at 4mg b.i.d.	Alosetron (only 5-HT3 antagonist approved in IBS-D) FDA warnings re ischemic colitis; use in F <65y
Somatostatin type 2 agonist	Octreotide approved as SQ/ IV administration for neuro-endocrine tumors	Rat IBS models: reduced sensation; single X-O RCT in 8 patients with IBS-D	Increased	Small RCT; dual effect; consider long-acting im monthly or octreotide SQ TID
Mast cell stabilizer	Ketotifen eyedrops approved for allergic conjunctivitis	Rat studies: affect afferents	Not studied	60 pt, 8-wk RCT; higher proportion of pts with > considerable relief of symptoms
Histamine H1 receptor antagonist	Ebastine (oral) approved outside for allergic conjunctivitis	Rat studies: affect afferents	Not studied	55 pt 12 wk RCT: increased % responders (at least considerable relief) and decreased abdo pain; 202 pt RCT in IBS-non-C: increased # responders global & pain
CGRP antagonist	Rimegepant approved for migraine	Reduced in rodent colon IBS models and IBS-non-C	Not increased	24 pt RCT: reduced rectal sensation, not pain
Cannabinoids	Several entities of which oral cannabidiol approved for epilepsy in childhood syndromes	Not studied	Not studied	RCTs: Palmitoylethanolamide; olorinab
GLP-1 agonist	Liraglutide approved for T2DM and obesity; Rose-010 (not approved)	GLP-1 affects visceral and somatic afferents IBS models	Not studied	2 RCTs ROSE-010 potential efficacy; controversial colonic transit effects

α2-adrenergic agonist, clonidine

Clonidine, in the dose range 0.1– 0.3 mg, was associated with changes in sensation of gas, urgency, and pain evoked by distentions of the colon and rectum in healthy volunteers. However, these effects may be related to both reduced afferent function and increased compliance.²⁴ In patients with IBS-D, IBS-C or IBS-mixed, 0.1 and 0.15 mg clonidine administered for 6 days reduced rectal pain sensation with 12–36 mmHg distensions only in IBS-C.²⁵ Adverse effects with oral clonidine (arterial hypotension, drowsiness, dry mouth, and sleep problems) reduces potential for IBS-pain relief. Studies are required with patch formulation releasing 0.1– 0.3 mg over 24h.

5-HT₃ antagonists

Rat colonic afferents can be selectively activated by 5-HT and by the selective 5-HT₃ receptor agonist, 2-methyl 5-HT. 5-HT₃ receptors were demonstrated in ~25% of lumbar DRG neurons in the rat.²⁶ The HT₃ receptor antagonist, alosetron (0.25 or 4mg b.i.d.), increased thresholds for first perception and pain with volume-based distentions in human colon.²⁷ However, alosetron, 4 mg b.i.d., increased colonic compliance,²⁷ suggesting that the reduced sensation may not reflect solely afferent effects. Nevertheless, clinical trial evidence shows beneficial effects of alosetron on pain associated with IBS (summarized in SRMAs^28,29). Other 5-HT₃ antagonists have documented efficacy in IBS, such as ondansetron in clinical trials,^30–32 meta-analysis,³¹ and in a real-world study.³³ The experimental medication, cilansetron, stimulated sigmoid contractility and induced firmer stool consistency in healthy human volunteers.³⁴ No clinical trials were reported for cilansetron in IBS.

Somatostatin type 2 receptor (SS2R) agonist

In an anesthetized rat model, the SS2R agonist, octreotide, dose- dependently inhibited mesenteric afferent nerve activity at baseline, and after high pressure distentions.³⁵ In rat jejunal hypersensitivity triggered by Cryptosporidium parvum intestinal infection (model of post-infectious IBS), octreotide reduced mast cell accumulations, nerve fiber densities, and hypersensitivity to distention.³⁶

A placebo-controlled crossover trial in 8 patients with IBS-D assessed 100 mcg octreotide which induced increased threshold volumes for first perception, pressure, urgency, and maximal tolerated volume during rectal distention, suggesting reduced sensation with increased rectal compliance, not restricted to effects on afferents.³⁷ Another study showed octreotide 1.25mcg/kg SQ significantly increased thresholds for visceral perception in IBS patients without modifying compliance during distension or colonic tone.³⁸ Further studies including approved long-acting somatostatin type 2 receptor agonists (used in patients with neuroendocrine tumors) may potentially treat pain particularly in IBS-D.

Mast cell stabilizer

Patients with IBS and rectal hypersensitivity have reduced numbers of mast cells on rectal biopsy. The mast cell stabilizer, ketotifen, was associated with a borderline increase in the threshold for discomfort (p=0.08) exclusively in patients with baseline rectal hypersensitivity (not with normal sensitivity). In 60 patients with IBS who underwent an 8-week trial, ketotifen was associated with a higher proportion with more than considerable relief of symptoms compared to placebo.³⁹ This benefit was shown to result from ketotifen’s histamine H₁ receptor antagonism.³⁹

Histamine H₁ receptor antagonist

TRPV1 sensitization of submucosal neurons by histamine is mediated via histamine-1R (HRH1). Histamine potentiates the number of responding DRG neurons through HRH1 receptors. In a placebo-controlled, 12-week trial of 55 patients with IBS, ebastine increased the proportion of responders (at least considerable relief) and decreased abdominal pain scores.⁴⁰ A subsequent trial⁴¹ of 202 participants with non-constipation IBS confirmed ebastine resulted in significantly more responders for global relief and abdominal pain intensity compared to placebo. The ketotifen and ebastine trials suggest that HRH1 antagonist approach may be promising for the treatment of pain in IBS. The development of new medications for IBS-pain is often determined by the observed NNT in a proof-of-concept phase 2A or 2B trial. Unfortunately, the NNT for ebastine was 12.5 which led to a discontinuation of the program. This is particularly challenging because of the diversity of mechanisms and psychosensory state of patients which may impact the assessment of efficacy in such phase 2A or 2B trials.

Calcitonin gene-related peptide antagonist

Calcitonin gene-related peptide (CGRP) is a neuropeptide expressed by visceral afferents originating from DRG. CGRP-expressing cells and receptors are present throughout the gastrointestinal system including the enteric nervous system, vasculature, muscle layers, mucosa, endocrine cells, and immune cells.

Stimulation of gut mucosa results in activation of intrinsic afferent pathways in submucosal ganglia, leading to activation of α-CGRP receptors in DRG.⁴² In addition, β-CGRP is released in the submucosal and myenteric plexuses. CGRP is also a transmitter in the sensory pathway mediating the peristaltic reflex.⁴³ In the DRG, CGRP immunoreactivity has been observed in most small-sized cells and in some intermediate- sized cells.⁴⁴ CGRP is also expressed in the spinal cord of several species.⁴⁴

A CGRP receptor antagonist reversed TNBS-induced colonic hypersensitivity in rodent models.⁴⁵ A placebo-controlled study in 24 patients with pain associated with non-C-IBS showed that the CGRP antagonist, rimegepant, resulted in higher threshold pressures for pain, reduced sensory ratings of gas, urgency, and pain during phasic distentions at 24 mmHg, and reduced sensory ratings of gas and urgency at 36 mmHg distentions, without any change in rectal compliance.⁴⁶ These data suggest that the CGRP antagonist selectively affects afferent functions.

Cannabinoid modulation

The endocannabinoid system targets visceral pain through effects on enterocytes, enteroendocrine cells, mucosal immune cells, or the DRG.⁴⁷ Delta-9-tetrahydrocannabinol did not result in any significant improvement compared to placebo for chronic abdominal pain, chronic pancreatitis pain, or chronic post-surgical pain.⁴⁸ However, palmitoylethanolamide, (structurally related to the endocannabinoid, anandamide) with polydatin was associated with a reduction in abdominal pain/discomfort severity in IBS.⁴⁹ Such benefit was not observed with a chewing gum formulation containing 50 mg cannabidiol (CBD) used on-demand for pain symptoms with a maximum of six per day.⁵⁰

Olorinab, a peripherally acting, full agonist of cannabinoid receptor 2, at a dose of 50 mg t.i.d., significantly reduced weekly average abdominal pain score in the subgroup (35/69) with highest baseline pain score (>6.5/10).⁵¹ Olorinab is no longer in development given that the primary endpoint [the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 1] was not met.

Further studies of cannabinoid modulation are required to prove efficacy and safety for this cannabinoid receptor modulation for IBS pain.

Nicotinic cholinergic modulation

The alpha-3 beta-4 nicotinic acetylcholine receptor (α3β4 AChR) mediates ganglionic neurotransmission in sympathetic and parasympathetic throughout the body, as well as enteric neurons; by inference, ‘ganglionic blockers’ at the α3β4 AChR receptors would have profound systemic effects. There are distinct neuronal α4β2, α5β2, and α6β2 AChRs. Among these, α6β2 AChR is expressed in a distinct class of colon-projecting DRGs in mice.⁵²

Varenicline, a partial agonist at α4β2 and α6β2 nAChRs,⁵³ is approved for the treatment of nicotine addiction. In adults with chronic pain undergoing medically-directed opioid detoxification, a pilot trial of varenicline showed decreased opioid withdrawal scores during opioid dose-tapering compared to placebo.⁵⁴ Given its effects on α6β2 nAChRs which are expressed in colon-projecting DRGs in mice, and the availability of the medication, it was considered an interesting mechanism to target IBS pain in humans. An open-label study in 8 participants with non-C IBS and chronic abdominal pain showed significant improvements in anxiety, daily abdominal pain scores, and bowel movement frequency with only minor effects of rectal sensation of urgency but not pain during balloon distention.⁵⁵ These results are consistent with central afferent modulation. Placebocontrolled trials of varenicline in IBS are required toevaluate effects on pain and to elucidate mechanism(s) involved.

K-Opioid receptor agonists

The three major opioid receptors, μ, κ and δ, are widely distributed in the central and peripheral nervous systems,⁵⁶ and κ receptors modulate visceral including gastrointestinal nociception.⁵⁷ κ-opioid receptors are upregulated in the presence of colonic inflammation; the mechanical and thermal sensitivity of polymodal pelvic nerve afferents from the rat colon can be inhibited by intracolonic instillation of κ-opioid agonist, asimadoline.⁵⁸ This effect was preserved in rat models with selective knockout of brain κ-opioid receptors suggesting peripheral action.⁵⁹ However, human trials of on-demand dosing during episodes of IBS pain⁶⁰ and a placebo-controlled trial of 0.15, 0.5, or 1.0 mg asimadoline b.i.d. for 12 weeks in 596 patients identified no significant treatment effects on IBS pain or discomfort.⁶¹ In a study of 20 patients with IBS, pharmacodynamic studies with single dose 0.5mg asimadoline showed reduced colonic pain intensity without altering compliance measured by intra-colonic barostat-controlled balloon.⁶² Asimadoline is no longer in development. However, given the evidence regarding κ-opioid receptors on afferent mechanisms, further studies with κ-opioid receptor agonists appear warranted.

Glucagon-like peptide 1

The adverse effects associated with tirzepatide or semaglutide include both diarrhea and constipation.⁶³ There is contradictory information on motility, based on human and rat studies. A retrospective case series using the wireless motility capsule documented prolonged whole gut transit time in 44% of patients treated with GLP-1 receptor agonists (RAs).⁶⁴ Conversely, liraglutide accelerated colonic transit in type 1 diabetes mellitus and polyneuropathy,⁶⁵ and GLP-1 accelerated colonic transit via central corticotropin-releasing factor (CRF) and peripheral vagal pathways in conscious rats.⁶⁶ Further studies of effects of GLP-1 RAs on colonic transit in IBS are necessary.

GLP-1 has very significant effects on sensory mechanisms, especially in DRG neurons and on multiple pain syndromes (summarized in Table 2).^67–71 GLP-1 RAs also relieve pain in diverse organ systems⁷² through neuroprotective and metabolic regulatory properties, e.g. inhibiting inflammation and oxidative stress, and promoting β-endorphin release.⁷²

Table 2.

Effects of GLP-1 on Sensory Mechanisms^67–7,1

Experimental model	Effects of GLP-1 or GLP-1 agonist	Reference
Cell viability in DRG neurons exposed to H2O2	GLP-1 RAs (exendin-4 and GLP-1) prevent reduction of cell viability and apoptosis	#67, Mohiuddin MS, et al. J Diabetes Res 2019:9426014
Chemotherapy (paclitaxel)-induced peripheral neuropathy	reduced the increased oxidative stress and inflammatory signals; increased β-endorphin and μ-opioid receptors through IL-10; increasing neurite length, promoting neuroregeneration; reduced the increased expression of the TRP family	#68, Jung Y, et al. Korean J Pain 2025;38: 267–281
Mechanisms in reducing neuropathic pain by GLP-1 RA	mitigate the inflammatory processes, decreasing cytokines TNF-α and IL-1β in mouse models of diabetic neuropathy; induce IL-10 (inhibitor of pro-inflammatory cytokines) expression in chronic pain models	#69, Kuthati Y, et al. Biomolecules 2025;26:15(5):622
Colonic-sensitized rat models	exendin-4 dose-dependently reduced visceral hypersensitivity by upregulating SERT and downregulating TPH- 1 expression	#70, Cui et al. Mol Med Rep 2020; 21:1934–40
Lipopolysaccharide or water-avoiding stress hypersensitivity in rats	liraglutide reduced visceral allodynia by suppressing pro-inflammatory cytokine production and improving colonic barrier integrity	#71, Nozu et al. J Gastroenterol Hepatol 2018;33:232–239

In experimental rat models of visceral hypersensitivity, the GLP-1 agonists reduced hypersensitivity by reducing mucosal 5-HT (upregulating mucosal serotonin transporter protein, and downregulating 5-HT synthesis),⁷⁰ as well as suppressing pro-inflammatory cytokines and reducing colonic permeability.⁷¹ However, it has also been reported that GLP-1 activates enterochromaffin cells to release 5-HT,⁷³ and therefore the precise role of 5-HT in any beneficial effects of GLP-1 on visceral sensitivity deserves further investigation.

Currently approved GLP-1 RAs cross the blood-brain barrier and can modulate central inflammatory pathways which sustain neuropathic pain in rodent models of diabetic neuropathy, and chronic pain models.⁶⁹

Human studies of analgesic effects of GLP-1 RAs in headache and pain disorders^74,75 or visceral pain have been extensively reviewed. including two RCTs of the effect of the GLP-1 RA, ROSE-010, in IBS, with greater efficacy among female patients.^74,76,77

Acid-Gated Ion Channels

Damaged tissues, as might occur in post-infectious IBS with a component of inflammation, are associated with low pH. Acid-sensing ion channels (ASIC) are a family of proton-gated channels expressed throughout the nervous system including DRG. A specific subtype, ASIC3 (also called DRASIC), is found in large diameter sensory neurons that may be mechanoreceptive,⁷⁸ and were documented in induction of mechanosensitivity of mouse colon afferents in visceral hypersensitivity involving inflammatory mediators.⁷⁹ Rat colonic hypersensitivity induced by butyrate enemas was associated with significant increase in nerve growth factor and ASIC1a protein expression in lumbosacral sensory neurons of rats.⁸⁰ A neonatal maternal deprivation (NMD) IBS model was also associated with up-regulation of ASIC1 protein expression in the spinal dorsal horn.⁸¹ The ASICs inhibitor amiloride (potassium-sparing diuretic) prevented the development of butyrate-induced CHS,⁸⁰ and reduced activation of dorsal horn neurons from NMD rats.⁸¹ In a zebrafish-based model of acute visceral pain induced by 2.5% acetic acid i.p., writhing-like responses (surrogate for pain) were abolished by amiloride.⁸² The potential efficacy of the approved medication, amiloride, has not been tested in human visceral pain or IBS (based on a literature and clinicaltrials.gov search).

Conclusions and a Look to the Future

Pharmacological modulation of peripheral visceral afferents and DRG represents a significant opportunity for advances in the management of IBS. It is important to note that the placebo-controlled studies conducted in humans that showed significant benefit with the medications (e.g. ebastine, rimegepant, ketotifen and Rose-010) have been relatively small, other medications tested in larger placebo-controlled trials were not significant (e.g. asimadoline, olorinab), and the effects of varenicline were observed in an open-label study. Therefore, the strongest evidence for targeting the visceral afferents and DRGs is still predominantly based on preclinical studies. However, a significant challenge in the demonstration of efficacy and regulatory approval of medications for IBS-pain is that there is a very substantial placebo effect (24.5% for abdominal pain in trials of drugs licensed for IBS)⁸³ as well as nocebo effects⁸⁴ on the pain endpoints in IBS trials, For example, in the trial of olorinab, 52.9% on placebo achieved the FDA-mandated 30% reduction in pain scores during the treatment period; consequently, trials using this pain endpoint need to be much larger than trials that use changes in bowel frequency or stool consistency as endpoints. It is also important to specify that preclinical models and small clinical trials document mechanistic plausability rather than demonstration of clinical efficacy.

Nevertheless, the unmet need requires dedication and commitment as well as novel approaches such as targeting the DRG receptors with peripherally-restricted medications to help relieve patients’ suffering. Promising agents in IBS include CGRP antagonists which present interesting actions on rectal sensations in IBS-pain, and GLP-1 receptor agonists which require further studies of rectal sensation and colonic transit, particularly in IBS-D with pain. However, it is also important to acknowledge that many or all of the classes of medications considered in this discussion of potential IBS therapies also affect other sensory mechanisms in the spinal cord or brain. Nevertheless, in the same way that peripherally active mu opiate receptor antagonists (methylnaltrexone, naloxegol, alvimopan and naldemedine) were developed to block peripheral effects of opiates such as in constipation while maintaining central analgesic effects, pharmaceutical chemistry may advance the field with medications directed at peripheral sensory mechanisms targeting the DRGs. The hypothesis that the DRG receptors constitute a clinically-relevant target for the relief of pain would require selective action on these receptors without affecting the same types of receptors in the spinal cord or brain. This hypothesis is intended to encourage pharmaceutical development to target peripheral receptors as mediators of afferent signaling; the hypothesis does not claim that the DRG is the critical pathological focus of IBS. The collaboration of basic and translational scientists and clinical trialists is required to advance this field targeting DRG receptors for relief of IBS pain, including addressing the anticipated regulatory, safety, and translational hurdles.

What You Need to Know.

Background:

Current medications approved for IBS target predominantly bowel dysfunction and central pain processes. The major unmet need in IBS is relief of IBS-related pain and to a lesser extent, diarrhea.

Findings:

Visceral afferents’ cell bodies in dorsal root ganglia have several receptors which are targeted pharmacologically in rodent IBS models and in clinical trials in patients with IBS to relieve pain. These mechanisms have been targeted by clonidine (α−2R), octreotide (SS-2R), ketotifen and ebastine (H1R), rimegepant (CGRPR), cannabinoids, varenicline (α6β2nAChR), and GLP-1 receptor agonists with evidence of reduced pain.

Implications for Patient Care:

Development of peripherally-restricted medications that target these receptors at the DRGs have potential for peripheral neuromodulation for IBS pain.