Abstract

GR 159897 is a potent, selective NK2 receptor antagonist with anxiolytic properties that inhibits the contraction of experimental animals’ tracheal and intestinal smooth muscle. This study evaluated its effects on stress hormones and cytokines in rats under repeated stress.

Methods: Wistar rats underwent water avoidance stress (WAS) and heterotypic stress (HS). Measurements included fecal pellet output, colorectal transit, and plasma levels of CTRH, ACTH, corticosterone (CORT), and cytokines.

Results: Control rats gained weight, while WAS rats lost weight. Stressed rats treated with GR 159897, increased weight significantly. In HS, there was no significant change in the body weight (BW), and the administration of GR 159897 resulted in a noticeable increase in BW. WAS and HS caused an increase in fecal pellet excretion output in animals, and GR159897 significantly reduced the average number of pellets in WAS animals. CRH levels were significantly different in WAS and HS groups compared to controls. GR 159897 reduced CRH in WAS rats. ACTH levels increased in stress-subjected groups, significantly in HS rats, but GR 159897 decreased its concentration in both stress groups. CORT levels indicated significant differences among the control, WAS, and HS groups. GR 159897 reduced CORT levels in WAS+GR group, but not statistically significant to WAS group. GR 159897 significantly reduced elevated IL-6 levels in stressed rats.

Conclusion: The ability of GR 159897 to reduce colorectal contractions, fecal pellet output, stress hormone levels, and proinflammatory cytokines leads us to conclude that NK2 receptor antagonists could help treat conditions like IBS or inflammatory bowel disease.

Abstract

Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.

Graphical abstract

Highlights

• IBS associated with immune-mediated peripheral neuropathies
• Risk increase observed across GBS-related outcomes
• No association found with classic GBS
• Supports gut–immune–neural interaction

Abstract

Background

Irritable bowel syndrome (IBS) is recognized as a systemic disorder involving gut–brain–immune axis dysregulation, but its long-term association with immune-mediated peripheral neuropathies, including Guillain–Barré syndrome (GBS), is unclear.

Methods

We conducted a nationwide retrospective cohort study using the Korean National Health Insurance database, including approximately 2 million adults from 2012 to 2023. Incident IBS cases were identified after a 3-year washout period and matched 1:2 with controls by age, sex, and health examination year. Primary outcomes were GBS immune-mediated peripheral neuropathies and GBS and related immune-mediated peripheral neuropathies defined by ICD-10 codes; classic GBS was a secondary outcome. Cox proportional hazards models were applied.

Results

Among 141,781 patients with IBS and matched controls, IBS was associated with increased risk of the primary outcomes (incidence rate ratio, 1.57; 95% CI, 1.48–1.66). In fully adjusted models, IBS remained associated with GBS immune-mediated peripheral neuropathies (adjusted HR, 1.58; 95% CI, 1.44–1.73) and GBS and related immune-mediated peripheral neuropathies (adjusted HR, 1.50; 95% CI, 1.37–1.65), but not with classic GBS (adjusted HR, 1.25; 95% CI, 0.55–2.87).

Conclusions

IBS was associated with increased long-term risk of GBS spectrum immune-mediated peripheral neuropathies, suggesting a potential association with systemic immune-related condition.

Abstract

The comorbidity of overactive bladder (OAB) and irritable bowel syndrome (IBS) presents a major clinical challenge, with the underlying neural and microbial mechanisms of the gut–bladder axis poorly understood. Here we aimed to delineate the complete causal pathway from a specific gut microorganism to bladder dysfunction and validate it as a therapeutic target. We combined analysis of human OAB–IBS cohorts with a postinflammatory mouse model, integrating retrograde neuronal tracing, multiomics (16S rDNA and metabolomics), fecal microbiota transplantation, urodynamics, dorsal root ganglion (DRG) electrophysiology and pharmacological and/or surgical interventions. We first confirmed a direct anatomical link, identifying dichotomized DRG neurons co-innervating the colon and bladder. Patients with OAB–IBS and mice exhibited a shared gut dysbiosis characterized by Akkermansia muciniphila enrichment. This comorbidity occurred in the absence of local bladder inflammation or urinary colonization with A. muciniphila, confirming a functional, noninfectious mechanism. Fecal microbiota transplantation of A. muciniphila or patient microbiota causally exacerbated visceral hypersensitivity, the OAB phenotype and DRG hyperexcitability. Mechanistically, A. muciniphila enrichment shunted host tryptophan metabolism toward the serotonin (5-HT) pathway. The resulting excess 5-HT acted on specifically upregulated colonic 5-HT3a receptors to drive neuronal sensitization. Crucially, pharmacological blockade of the colonic 5-HT3a receptor or surgical severing of the mesenteric nerves reversed the bladder dysfunction and visceral hypersensitivity. Our findings delineate a novel pathway wherein A. muciniphila drives functional gut–bladder comorbidity by promoting a gut-derived serotonergic signal that sensitizes shared afferent neurons, establishing the gut-specific 5-HT3a receptor as a key, druggable therapeutic target.

Dr. Falk Pharma and Renexxion announce positive results on naronapride in gastroparesis from the global phase 2b MOVE-IT trial

• MOVE-IT met the primary endpoint with statistically significant improvement in gastroparesis symptoms in 20 mg and 40 mg TID doses vs placebo
• Improvements observed across key symptoms, including nausea, early satiety, post-prandial fullness and upper abdominal pain
• Favorable safety and tolerability profiles
• Late-breaking oral presentation delivered at Digestive Disease Week (DDW) 2026 in Chicago, IL.

 

Freiburg, Germany and Roscrea, Ireland – May 4, 2026 - Dr. Falk Pharma GmbH (“Dr. Falk Pharma”), a research-based pharmaceutical company specializing in digestive and metabolic medicine, and Renexxion Ireland Limited (“Renexxion”), a clinical-stage biopharmaceutical company, today announced positive results from MOVE-IT (NCT05621811), a global Phase 2b, randomized placebo-controlled trial evaluating the efficacy, safety, and tolerability of naronapride in adults with gastroparesis.

The double-blind, multicenter, 12-week study enrolled 328 adults with moderate-to-severe idiopathic or diabetic gastroparesis symptoms and objective evidence of delayed gastric emptying. Eligible patients received either 10 mg, 20 mg, 40 mg naronapride, or placebo, administered orally three times a day (TID) for 12 weeks. 

MOVE-IT met the primary endpoint, demonstrating statistically significant improvement versus placebo in the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD) Core Symptom Score in the 20 mg TID (p=0.0046) and 40 mg TID (p=0.0156) groups. The ANMS GCSI-DD is a content-validated, patient-reported outcome instrument that assesses the five cardinal gastroparesis symptoms: nausea, vomiting, early satiety, postprandial fullness and upper abdominal pain.

Abstract

Background: Visceral hypersensitivity and impaired intestinal barrier function are hallmark features of irritable bowel syndrome (IBS), linked to activation of corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine pathways. Cimetidine, a classical H2 blocker, has been shown to inhibit Na+/H+ exchangers (NHEs), thereby potentially suppressing proinflammatory cytokine release.

Objectives: This study examined whether cimetidine alleviates visceral hypersensitivity and colonic hyperpermeability in rat models of IBS.

Methods: Visceral pain threshold in response to colonic balloon distention was assessed by electromyographic detection of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured using Evans blue uptake in LPS- and CRF-induced IBS models in male Sprague-Dawley rats.

Results: Intragastric cimetidine (20-100 mg/kg daily for 3 days) prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently and also attenuated CRF-induced changes. In contrast, famotidine, another H2 blocker, did not replicate these effects. Amiloride, an NHE inhibitor, mimicked cimetidine's effects, both of which were abolished by intracisternal SB-334867, an orexin 1 receptor antagonist. Furthermore, atropine, sulpiride, and NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, but not scopolamine butylbromide, a peripheral muscarinic receptor antagonist, or domperidone, a peripheral dopamine D2 receptor antagonist, blocked cimetidine's action.

Conclusion: These findings suggest that cimetidine prevents visceral hypersensitivity and colonic hyperpermeability in IBS models through mechanisms involving central orexin signaling possibly triggered by NHE inhibition, NO, and central muscarinic and dopamine D2 receptor pathways. These findings may provide a basis for future therapeutic approaches targeting IBS.

Abstract

Objective To determine the prevalence of malaria co-infection among patients with irritable bowel syndrome (IBS) in Yemen and to evaluate the association of systemic inflammatory biomarkers (neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV) and platelet-to-lymphocyte ratio (PLR)) with this co-infection.

Design Multicentre, cross-sectional observational study conducted between April and December 2024.

Setting Primary and secondary healthcare facilities across 21 governorates in Yemen.

Participants 142 consecutive adult patients (aged 18–70 years) diagnosed with IBS according to the Rome IV criteria.

Outcome measures The primary outcome was the prevalence of malaria infection, confirmed by a rapid diagnostic test . Secondary outcomes included differences in NLR, MPV and PLR between groups, assessed using independent t-tests, and the diagnostic performance of these biomarkers evaluated by receiver operating characteristic curve analysis with AUC calculation. Multivariate binary logistic regression was used to identify independent predictors of malaria co-infection, adjusting for potential confounders.

Results The mean age was 42.3 years (SD 11.7) with an equal gender distribution. The prevalence of malaria co-infection was 45.1% (64/142). Patients with malaria positivity had significantly higher NLR (mean difference 0.56, 95% CI 0.40 to 0.72; p<0.001) and PLR (mean difference 22.6, 95% CI 17.8 to 27.4; p<0.001) and lower MPV (mean difference −0.60 fL, 95% CI −0.77 to −0.43; p<0.001) compared with malaria-negative patients. In adjusted logistic regression, higher NLR (adjusted OR 3.21, 95% CI 1.89 to 5.45) and PLR (adjusted OR per 10-unit increase 4.02, 95% CI 2.24 to 7.18) were independently associated with malaria positivity.

Conclusions Nearly half of the Yemeni patients with IBS in this study had malaria co-infection, with the highest burden in diarrhoea-predominant and mixed subtypes. Elevated NLR and PLR were strongly associated with co-infection, suggesting these readily available biomarkers could aid targeted screening in resource-limited, endemic settings.

May 5, 2026

• Topline results expected Q3 2026

WATERTOWN, Mass. – May 5, 2026 – Nocion Therapeutics, Inc., a biopharmaceutical company developing novel small molecule therapies that selectively silence activated sensory neurons, today announced that its Phase 2b ASPIRE trial evaluating taplucainium for the treatment of refractory or unexplained chronic cough (rCC/uCC) is fully enrolled.

“Fully enrolling the Phase 2b ASPIRE trial represents a major milestone on the path to delivering a transformative new therapy for patients with chronic cough,” said Matthew Frankel, M.D., MBA, Chief Medical Officer of Nocion Therapeutics. “Taplucainium’s differentiated mechanism has the potential to deliver fast-acting and long-lasting relief by addressing the underlying drivers of chronic cough. The rapid pace of enrollment underscores the strong demand among clinicians and patients for a safe and effective treatment for this undertreated, debilitating condition. With the Phase 2b trial now fully enrolled, we are on track to report topline data in Q3 2026 to support a potential registrational program for taplucainium.”

ASPIRE is a Phase 2b, randomized, double-blind, placebo-controlled study investigating the efficacy, safety, and tolerability of taplucainium inhalation powder once daily in adults with rCC/uCC. The study has reached its target enrollment of 240 patients across more than 100 sites in the U.S., Canada, U.K. and EU. Patients were randomized into one of four groups either receiving taplucainium 1 mg, 3 mg, 6 mg, or placebo over 1 month of treatment. The primary endpoint is the change in 24-hour coughs per hour from baseline to end of treatment (as measured by VitaloJAK® Cough Counts). Key secondary endpoints include change in awake coughs, cough severity, and urge to cough.

Additional information about the ongoing ASPIRE study can be found at clinicaltrials.gov (Identifier: NCT06504446).

Abstract

Background: Obesity and diabetes are associated with altered gastrointestinal function and with the development of abdominal pain, nausea, diarrhea, and constipation among other symptoms. The enteric nervous system (ENS) regulates gastrointestinal motility. Enteric neuropathies defined as damage or loss of enteric neurons can lead to motility disorders.

Purpose: Here, we review the molecular mechanisms that drive enteric neurodegeneration in diabetes and obesity, including signaling pathways leading to neuronal cell death, oxidative stress, and microbiota alteration. We also highlight potential approaches to treat enteric neuropathies including antioxidant therapy to prevent oxidative stress-induced damage and the use of stem cells.

Figure 1: https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31f9/11807233/95ef78a42ee9/nihms-2015146-f0001.jpg

Abstract

Background and aims: A substantial proportion of persons with inflammatory bowel disease (IBD) in remission continue to experience abdominal pain, altered bowel habits, and bloating that resemble irritable bowel syndrome (IBS). Lack of standardized definitions and evidence-based management strategies leads to diagnostic ambiguity and potentially unnecessary escalation of IBD therapy. A joint Rome Foundation/International Organization for the Study of Inflammatory Bowel Disease Working Team developed consensus recommendations on nomenclature, evaluation, and treatment of IBD with IBS-like symptoms.

Methods: A multidisciplinary international panel applied a modified RAND/UCLA Appropriateness Method. Systematic literature reviews informed statement generation across multiple domains: nomenclature, diagnostic and symptom assessment, dietary therapies, drugs, and brain-gut behavioral therapies. Panelists rated the appropriateness of candidate statements independently on a 9-point Likert scale, followed by anonymized feedback, discussion, and re-voting across two iterative rounds.

Results: Thirteen panelists reviewed 133 initial statements; 105 proceeded to final scoring. Of these, 86 were rated appropriate, 16 uncertain, and 3 inappropriate. The preferred term was "IBD with IBS-like symptoms," defined as abdominal pain, bowel habit change, and/or bloating not explained by active inflammation or structural disease. For clinical care, diagnosis should combine Rome clinical criteria with objective exclusion of inflammation. For research, candidate thresholds for endoscopic, histologic, biomarker, and imaging remission were endorsed. Appropriate therapies included psyllium (if no stricture), a short-term low FODMAP diet, targeted drugs, and brain-gut behavioral therapies.

Conclusion: This first joint consensus provides standardized terminology, evaluation strategies, and treatment recommendations for IBD with IBS-like symptoms, supporting improved clinical management and guiding future mechanistic and therapeutic research.

Highlights

•Protease-activated receptor-2 (PAR2) knockout models suggest that PAR2 is an important pain target.

•C781 is a β-arrestin biased antagonist at PAR2 that blocks protease-evoked nociception in mice.

•C781 can reverse protease-evoked nociception when given after protease treatment.

•The biased antagonism of C781 can improve safety profiles of PAR2 antagonists for pain treatment.

•C781 pharmacokinetics needs to be improved for further development.

Abstract

Given the limited options and often harmful side effects of current analgesics and the suffering caused by the opioid crisis, new classes of pain therapeutics are needed. Protease-activated receptors (PARs), particularly PAR2, are implicated in a variety of pathologies, including pain. Since the discovery of the role of PAR2 in pain, development of potent and specific antagonists has been slow. In this study, we describe the in vivo characterization of a novel small molecule/peptidomimetic hybrid compound, C781, as a β-arrestin-biased PAR2 antagonist. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. Pharmacokinetic studies were done to assess pharmacokinetic/pharmacodynamic relationship in vivo. We used both prevention and reversal paradigms with protease treatment to determine whether C781 could attenuate protease-evoked pain. C781 effectively prevented and reversed mechanical and spontaneous nociceptive behaviors in response to small molecule PAR2 agonists, mast cell activators, and neutrophil elastase. The ED50 of C781 (intraperitoneal dosing) for inhibition of PAR2 agonist (20.9 ng 2-AT)-evoked nociception was 6.3 mg/kg. C781 was not efficacious in the carrageenan inflammation model. Pharmacokinetic studies indicated limited long-term systemic bioavailability for C781 suggesting that optimizing pharmacokinetic properties could improve in vivo efficacy. Our work demonstrates in vivo efficacy of a biased PAR2 antagonist that selectively inhibits β-arrestin/MAPK signaling downstream of PAR2. Given the importance of this signaling pathway in PAR2-evoked nociception, C781 exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development.

Perspective

Our work provides evidence that PAR2 antagonists that only block certain aspects of signaling by the receptor can be effective for blocking protease-evoked pain in mice. This is important because it creates a rationale for developing safer PAR2-targeting approaches for pain treatment.

Abstract

Background & Aims

Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as G protein-coupled receptor 68 (GPR68), a proton-sensing G protein-coupled receptor (GPCR) expressed on immune and stromal cells. Single-cell RNA sequencing (RNA-seq) analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.

Methods

Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNA-seq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca^(2+) imaging in DRG neurons from wild-type and GPR68^(-/-) mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).

Results

RNA-seq analysis showed GPR68 is robustly expressed in Trpv1^(+) colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68^(-/-) mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca^(2+)-free buffer, dorsal root ganglion neurons from GPR68^(-/-) mice or those pretreated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca^(2+) responses. By contrast, the colonic afferent and dorsal root ganglion Ca^(2+) response (in Ca^(2+)-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68^(-/-) mice highlighting the involvement of divergent proton-dependent cellular signaling cascades.

Conclusions

These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.

Graphical abstract

ABSTRACT

Background

Gut-directed hypnotherapy is an effective treatment for patients with irritable bowel syndrome (IBS). Group delivery and nurse-led hypnotherapy can increase availability. Online treatment shows promising results, but this has not been tested in a group format.

Aims

To investigate the acceptability and efficacy of nurse-led, online group hypnotherapy in patients with IBS.

Methods

Patients received eight sessions of gut-directed hypnotherapy in groups via live video conferencing. IBS symptoms were assessed at baseline, mid-treatment, after treatment, and at follow-up. Patients who reported an IBS-SSS reduction of ≥ 50 points were considered responders. Extracolonic symptoms, psychological symptoms, and quality of life were assessed, as well as usability and treatment satisfaction. The study results were compared to previous assessments of group hypnotherapy delivered on-site. After hypnotherapy, patients were asked which treatment modality (online or on-site) they would prefer.

Results

We included 51 patients. IBS severity was reduced after hypnotherapy (median IBS-SSS: 304 (225–385) vs. 225 (172–312), p < 0.001), and 27 patients (53%) were responders. These results are comparable to on-site group hypnotherapy outcomes; IBS-SSS: 310 (232–368) versus 230 (151–330), p < 0.001, responders: 55%. Symptom reduction was sustained at six-month follow-up. Quality of life, extracolonic, and psychological symptoms also improved. The patient ratings of the usability of the video call platform and treatment satisfaction were high.

Conclusions and Inferences

Nurse-led, gut-directed group hypnotherapy delivered online is acceptable, often preferred by patients, and has comparable efficacy to in-person group hypnotherapy. By combining group and online treatment, hypnotherapy can be made more accessible for patients.

Key Points

• Gut-directed hypnotherapy is a brain–gut behavioral therapy that is effective for patients with irritable bowel syndrome, but access to treatment is limited.
• In this pilot study, we tested to give nurse-led group hypnotherapy using a digital video platform to increase accessibility further.
• Study outcomes show that the treatment modality is feasible, efficacious, and acceptable for patients.

Abstract

Background and aims: Irritable bowel syndrome (IBS) is a prevalent disorder of gut-brain interactions, while the pathophysiology is intricate and current treatments mainly focus on improving symptoms. Our study aims to explore potential drug targets for IBS using Mendelian randomization (MR) analysis.

Methods: Firstly, we integrated 1443 plasma and 151 cerebrospinal fluid (CSF) proteins with the largest IBS genome-wide association study (GWAS) dataset for MR analysis, and validated the findings in the FinnGen cohorts. The robustness of the results was then corroborated through reverse causality detection and Bayesian colocalization. Secondly, we performed mediation analysis to explore whether psychiatric disorders mediate the association between IBS and the identified protein. Finally, we performed druggability assessment investigate the potential mechanisms and medicinal value of the target.

Results: The MR analysis indicated that LRP8 deficiency in both plasma and CSF was linked to a higher risk of IBS. Sensitivity analyses provided strong support for the finding. Additionally, schizophrenia mediates a small portion of this causal relationship. LRP8 exhibited strong and stable affinity with several small molecular compounds in molecular docking, revealing the potential of LRP8 as the novel drug target for IBS.

Conclusions: The study suggests that LRP8 in both plasma and CSF has a causal relationship with IBS. This relationship provides novel mechanistic insights into the complex pathophysiology of brain-gut interactions in IBS, and LRP8 has the potential to be a drug target.

Abstract

Neonatal colorectal distension (CRD), as a mechanical stress stimulus in early life to simulate irritable bowel syndrome (IBS), increases susceptibility to visceral pain and depression-like behaviors in adulthood. Enriched environment (EE) treatment effectively counteracts these effects, but the underlying neural circuit and molecular mechanisms remain poorly defined. Here, we investigate whether EE reverses visceral pain and depression by modulating cannabinoid type-1 receptors (CB1Rs) in the PrLGlu→avBNST pathway. A multidisciplinary combination of behaviors, chemogenetics, optogenetics, pharmacology, molecular and electrophysiological approaches is applied. In CRD rats, CB1Rs-expressing glutamatergic neurons in prelimbic cortex (PrL) projecting to the anteroventral bed nucleus of the stria terminalis (avBNST) promote visceral pain and depression. EE exerts analgesic and antidepressant effects by rescuing PrLGlu→avBNSTGABA pathway activity and reducing CB1Rs expression. EE also reverses the CRD-induced paraventricular nucleus (PVN) hyperactivity by reversing the dysfunction of this pathway. Together, EE alleviates chronic visceral pain and comorbid depression by restoring homeostasis in the CB1Rs-modulated PrLGlu→avBNSTGABA→PVN pathway. Combining EE and CB1Rs-targeted pharmacological modulation offers a promising therapeutic strategy for early-life developmental disorder-related pain-depression comorbidities.