{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:02:59Z","timestamp":1790877779721,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There is an urgent need for analgesics to treat pain that lacks the serious side effects of existing drugs, such as conventional opioids and nonsteroidal anti-inflammatory drugs. Most side effects arise from the non-selective actions of these drugs at sites where the pain is not generated because of the ubiquitous expression of the drug targets in the body regardless of the underlying disease. In this narrative review, we explore 2 mechanistic approaches focusing on visceral nociceptive neurons that have the potential to limit side effects while preserving efficacy. Strategy 1 demonstrates how mechanistic pain studies underlying a specific disorder, such as irritable bowel syndrome, can identify targets specifically upregulated in that condition. We discuss recent findings regarding 2 neuroactive mediators, histamine and proteases, including novel intestinal sources, signalling pathways, and intracellular synergistic actions that could serve as potential therapeutic targets. Strategy 2 examines how acidic microenvironments unique to the sites of inflammation where pain is generated, such as in inflammatory bowel disease, can be exploited. pH-sensitive analgesics have been developed that inhibit \u03bc-opioid receptors at sites of inflammation where tissue pH is low, ie, 6.5, while showing no activity at other sites where tissue pH is normal, ie, 7.4. Collectively, these studies highlight the value of investigating the mechanisms underlying specific disorders, which can lead to novel biomarkers and therapeutic strategies that can enhance the specificity of the new therapies.<\/jats:p>","DOI":"10.1093\/jcag\/gwaf016","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T07:41:41Z","timestamp":1752738101000},"page":"152-162","source":"Crossref","is-referenced-by-count":2,"title":["Emerging therapeutic approaches for treating abdominal pain"],"prefix":"10.1093","volume":"8","author":[{"given":"Nestor N","family":"Jimenez-Vargas","sequence":"first","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Parkar","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaede","family":"Takami","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah M","family":"Wood","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan E","family":"Lomax","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Reed","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-9948","authenticated-orcid":false,"given":"Stephen J","family":"Vanner","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, Kingston Health Sciences Centre, Queen\u2019s University , 76 Stuart Street, Kingston, Ontario K7L 2V7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"issue":"5","key":"2025102413220596300_CIT0001","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1155\/2015\/918976","article-title":"Supporting chronic pain management across provincial and territorial health systems in Canada: findings from two stakeholder dialogues","volume":"20","author":"Wilson","year":"2015","journal-title":"Pain Res Manag."},{"issue":"5","key":"2025102413220596300_CIT0002","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1155\/2012\/861478","article-title":"Canadian digestive health foundation public impact series 3: irritable bowel syndrome in Canada. Incidence, prevalence, and direct and indirect economic impact","volume":"26","author":"Fedorak","year":"2012","journal-title":"Can J Gastroenterol."},{"key":"2025102413220596300_CIT0003","author":"Hatt","year":"2022"},{"issue":"12","key":"2025102413220596300_CIT0004","first-page":"3","article-title":"Significant factors associated with problematic use of opioid pain relief medications among the household population, Canada, 2018","volume":"33","author":"Carri\u00e8re","year":"2022","journal-title":"Health Rep"},{"key":"2025102413220596300_CIT0005","author":"Statistics Canada","year":"2019"},{"issue":"6","key":"2025102413220596300_CIT0006","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1053\/j.gastro.2024.01.045","article-title":"Chronic visceral pain: new peripheral mechanistic insights and resulting treatments","volume":"166","author":"Ford","year":"2024","journal-title":"Gastroenterology."},{"issue":"4","key":"2025102413220596300_CIT0007","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1111\/nmo.12316","article-title":"Using human intestinal biopsies to study the pathogenesis of irritable bowel syndrome","volume":"26","author":"Nasser","year":"2014","journal-title":"Neurogastroenterol Motil."},{"issue":"11","key":"2025102413220596300_CIT0008","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/s41577-022-00700-9","article-title":"Immune activation in irritable bowel syndrome: what is the evidence","volume":"22","author":"Aguilera-Lizarraga","year":"2022","journal-title":"Nat Rev Immunol."},{"issue":"3","key":"2025102413220596300_CIT0009","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/1751-2980.12971","article-title":"The role of intestinal mast cell infiltration in irritable bowel syndrome","volume":"22","author":"Cheng","year":"2021","journal-title":"J Dig Dis."},{"issue":"4","key":"2025102413220596300_CIT0010","doi-asserted-by":"publisher","first-page":"463","DOI":"10.15403\/jgld-229","article-title":"Mast cells in irritable bowel syndrome: a systematic review","volume":"28","author":"Krammer","year":"2019","journal-title":"J Gastrointestin Liver Dis."},{"issue":"3","key":"2025102413220596300_CIT0011","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1053\/j.gastro.2003.11.055","article-title":"Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome","volume":"126","author":"Barbara","year":"2004","journal-title":"Gastroenterology."},{"issue":"7","key":"2025102413220596300_CIT0012","doi-asserted-by":"publisher","first-page":"e14339","DOI":"10.1111\/nmo.14339","article-title":"Mast cell mediation of visceral sensation and permeability in irritable bowel syndrome","volume":"34","author":"Hasler","year":"2022","journal-title":"Neurogastroenterol Motility"},{"issue":"4","key":"2025102413220596300_CIT0013","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/s0306-4522(99)00377-2","article-title":"Changes in afferent impulse activity of small intestine mesenteric nerves in response to antigen challenge","volume":"94","author":"Nozdrachev","year":"1999","journal-title":"Neuroscience."},{"issue":"1","key":"2025102413220596300_CIT0014","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1053\/j.gastro.2006.11.039","article-title":"Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome","volume":"132","author":"Barbara","year":"2007","journal-title":"Gastroenterology."},{"issue":"5","key":"2025102413220596300_CIT0015","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/s0016-5085(97)70056-8","article-title":"Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations","volume":"112","author":"Bueno","year":"1997","journal-title":"Gastroenterology."},{"issue":"4","key":"2025102413220596300_CIT0016","doi-asserted-by":"publisher","first-page":"G675","DOI":"10.1152\/ajpgi.1998.275.4.G675","article-title":"Histamine sensitivity of mesenteric afferent nerves in the rat jejunum","volume":"275","author":"Kreis","year":"1998","journal-title":"Am J Physiol."},{"issue":"10","key":"2025102413220596300_CIT0017","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1111\/bph.12641","article-title":"Transient receptor potential cation channels in visceral sensory pathways","volume":"171","author":"Blackshaw","year":"2014","journal-title":"Br J Pharmacol."},{"issue":"4","key":"2025102413220596300_CIT0018","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1053\/j.gastro.2015.12.034","article-title":"Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome","volume":"150","author":"Wouters","year":"2016","journal-title":"Gastroenterology."},{"issue":"3","key":"2025102413220596300_CIT0019","doi-asserted-by":"publisher","first-page":"G338","DOI":"10.1152\/ajpgi.00116.2018","article-title":"Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome","volume":"316","author":"Balemans","year":"2019","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"issue":"3","key":"2025102413220596300_CIT0020","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1136\/gutjnl-2023-331634","article-title":"Treatment of non-constipated irritable bowel syndrome with the histamine 1 receptor antagonist ebastine: a randomised, double-blind, placebo-controlled trial","volume":"73","author":"Decraecker","year":"2024","journal-title":"Gut."},{"issue":"1","key":"2025102413220596300_CIT0021","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1152\/physrev.00044.2021","article-title":"Protease-activated receptors in health and disease","volume":"103","author":"Peach","year":"2023","journal-title":"Physiol Rev."},{"issue":"4","key":"2025102413220596300_CIT0022","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1124\/pr.115.010991","article-title":"Proteinases, their extracellular targets, and inflammatory signaling","volume":"68","author":"Ramachandran","year":"2016","journal-title":"Pharmacol Rev."},{"issue":"6","key":"2025102413220596300_CIT0023","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.coph.2004.08.004","article-title":"Protease-activated receptors: protease signaling in the gastrointestinal tract","volume":"4","author":"Amadesi","year":"2004","journal-title":"Curr Opin Pharmacol."},{"issue":"10","key":"2025102413220596300_CIT0024","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1136\/gutjnl-2016-312094","article-title":"Epithelial expression and function of trypsin-3 in irritable bowel syndrome","volume":"66","author":"Rolland-Fourcade","year":"2017","journal-title":"Gut."},{"issue":"3","key":"2025102413220596300_CIT0025","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.pharmthera.2009.05.004","article-title":"Protease-activated receptors as drug targets in inflammation and pain","volume":"123","author":"Vergnolle","year":"2009","journal-title":"Pharmacol Ther."},{"issue":"3","key":"2025102413220596300_CIT0026","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1172\/JCI29255","article-title":"Role for protease activity in visceral pain in irritable bowel syndrome","volume":"117","author":"Cenac","year":"2007","journal-title":"J Clin Invest."},{"issue":"17","key":"2025102413220596300_CIT0027","doi-asserted-by":"publisher","first-page":"3516","DOI":"10.1111\/bph.14396","article-title":"Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post-inflammatory rat model for irritable bowel syndrome","volume":"175","author":"Ceuleers","year":"2018","journal-title":"Br J Pharmacol."},{"issue":"9","key":"2025102413220596300_CIT0028","doi-asserted-by":"publisher","first-page":"gutjnl","DOI":"10.1136\/gutjnl-2022-327260","article-title":"Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain","volume":"72","author":"Tuck","year":"2022","journal-title":"Gut."},{"issue":"Pt.3","key":"2025102413220596300_CIT0029","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1113\/jphysiol.2006.126599","article-title":"Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon","volume":"580","author":"Kayssi","year":"2007","journal-title":"J Physiol."},{"issue":"11","key":"2025102413220596300_CIT0030","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1111\/j.1365-2982.2009.01353.x","article-title":"Activation of protease-activated receptor-4 inhibits the intrinsic excitability of colonic dorsal root ganglia neurons","volume":"21","author":"Karanjia","year":"2009","journal-title":"Neurogastroenterol Motil."},{"issue":"3","key":"2025102413220596300_CIT0031","doi-asserted-by":"crossref","first-page":"G315","DOI":"10.1152\/ajpgi.2001.280.3.G315","article-title":"Stress and the castrointestinal tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance","volume":"280","author":"Collins","year":"2001","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"key":"2025102413220596300_CIT0032","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3389\/fnsys.2017.00086","article-title":"Stress-induced chronic visceral pain of gastrointestinal origin","volume":"11","author":"Greenwood-Van Meerveld","year":"2017","journal-title":"Front Syst Neurosci."},{"issue":"4","key":"2025102413220596300_CIT0033","doi-asserted-by":"publisher","first-page":"G1033","DOI":"10.1152\/ajpgi.00507.2007","article-title":"Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats","volume":"294","author":"Larauche","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"issue":"3","key":"2025102413220596300_CIT0034","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1111\/j.1365-2982.2011.01840.x","article-title":"Peripheral \u03b1-helical CRF (9-41) does not reverse stress-induced mast cell dependent visceral hypersensitivity in maternally separated rats","volume":"24","author":"van den Wijngaard","year":"2012","journal-title":"Neurogastroenterol Motil."},{"issue":"7844","key":"2025102413220596300_CIT0035","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/s41586-020-03118-2","article-title":"Local immune response to food antigens drives meal-induced abdominal pain","volume":"590","author":"Aguilera-Lizarraga","year":"2021","journal-title":"Nature."},{"key":"2025102413220596300_CIT0036","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2025.01.246","article-title":"Psychological stress-induced local immune response to food antigens increases pain signaling across the gut in mice","author":"Aguilera-Lizarraga","year":"2025","journal-title":"Gastroenterol"},{"issue":"655","key":"2025102413220596300_CIT0037","doi-asserted-by":"publisher","first-page":"eabj1895","DOI":"10.1126\/scitranslmed.abj1895","article-title":"Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice","volume":"14","author":"De Palma","year":"2022","journal-title":"Sci Transl Med."},{"issue":"7","key":"2025102413220596300_CIT0038","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1136\/gutjnl-2015-311339","article-title":"FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial","volume":"66","author":"McIntosh","year":"2017","journal-title":"Gut."},{"issue":"1\u20132","key":"2025102413220596300_CIT0039","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.pain.2009.04.017","article-title":"Fecal proteases from diarrheic-IBS and ulcerative colitis patients exert opposite effect on visceral sensitivity in mice","volume":"144","author":"Annahazi","year":"2009","journal-title":"Pain."},{"issue":"8","key":"2025102413220596300_CIT0040","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1038\/ajg.2013.152","article-title":"Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS","volume":"108","author":"Annahazi","year":"2013","journal-title":"Am J Gastroenterol."},{"key":"2025102413220596300_CIT0041","doi-asserted-by":"publisher","first-page":"19399","DOI":"10.1038\/srep19399","article-title":"Anti-nociceptive effect of Faecalibacterium prausnitzii in non-inflammatory IBS-like models","volume":"6","author":"Miquel","year":"2016","journal-title":"Sci Rep."},{"issue":"48","key":"2025102413220596300_CIT0042","doi-asserted-by":"publisher","first-page":"11758","DOI":"10.1523\/JNEUROSCI.1672-17.2017","article-title":"Protease-mediated suppression of DRG neuron excitability by commensal bacteria","volume":"37","author":"Sessenwein","year":"2017","journal-title":"J Neurosci."},{"issue":"4","key":"2025102413220596300_CIT0043","doi-asserted-by":"publisher","first-page":"101334","DOI":"10.1016\/j.jcmgh.2024.03.006","article-title":"Protease-induced excitation of dorsal root ganglion neurons in response to acute perturbation of the gut microbiota Is associated with visceral and somatic hypersensitivity","volume":"18","author":"Baker","year":"2024","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"1","key":"2025102413220596300_CIT0044","doi-asserted-by":"publisher","first-page":"2181922","DOI":"10.1080\/19490976.2023.2181922","article-title":"The emerging roles of bacterial proteases in intestinal diseases","volume":"15","author":"Caminero","year":"2023","journal-title":"Gut Microbes"},{"issue":"31","key":"2025102413220596300_CIT0045","doi-asserted-by":"publisher","first-page":"E7438","DOI":"10.1073\/pnas.1721891115","article-title":"Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome","volume":"115","author":"Jimenez-Vargas","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"5","key":"2025102413220596300_CIT0046","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1136\/gutjnl-2020-321193","article-title":"Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system","volume":"70","author":"Gottesman-Katz","year":"2021","journal-title":"Gut."},{"issue":"392","key":"2025102413220596300_CIT0047","doi-asserted-by":"publisher","first-page":"eaal3447","DOI":"10.1126\/scitranslmed.aal3447","article-title":"Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief","volume":"9","author":"Jensen","year":"2017","journal-title":"Sci Transl Med."},{"issue":"10","key":"2025102413220596300_CIT0048","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.tips.2018.08.003","article-title":"Therapeutic targeting of endosomal G-protein-coupled receptors","volume":"39","author":"Thomsen","year":"2018","journal-title":"Trends Pharmacol Sci."},{"issue":"46","key":"2025102413220596300_CIT0049","doi-asserted-by":"publisher","first-page":"12309","DOI":"10.1073\/pnas.1706656114","article-title":"Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission","volume":"114","author":"Yarwood","year":"2017","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"4","key":"2025102413220596300_CIT0050","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.cell.2016.07.004","article-title":"GPCR-G protein-beta-arrestin super-complex mediates sustained G protein signaling","volume":"166","author":"Thomsen","year":"2016","journal-title":"Cell."},{"issue":"26","key":"2025102413220596300_CIT0051","doi-asserted-by":"publisher","first-page":"15281","DOI":"10.1073\/pnas.2000500117","article-title":"Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain","volume":"117","author":"Jimenez-Vargas","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025102413220596300_CIT0052","doi-asserted-by":"publisher","first-page":"122874","DOI":"10.1016\/j.biomaterials.2024.122874","article-title":"PAR(2) on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451","volume":"314","author":"Bhansali","year":"2025","journal-title":"Biomaterials."},{"issue":"22","key":"2025102413220596300_CIT0053","doi-asserted-by":"publisher","first-page":"e2220979120","DOI":"10.1073\/pnas.2220979120","article-title":"Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief","volume":"120","author":"Hegron","year":"2023","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2025102413220596300_CIT0054","doi-asserted-by":"publisher","first-page":"121536","DOI":"10.1016\/j.biomaterials.2022.121536","article-title":"Sustained endosomal release of a neurokinin-1 receptor antagonist from nanostars provides long-lasting relief of chronic pain","volume":"285","author":"Latorre","year":"2022","journal-title":"Biomaterials."},{"issue":"24","key":"2025102413220596300_CIT0055","doi-asserted-by":"publisher","first-page":"5390","DOI":"10.1039\/d3tb00156c","article-title":"Targeting endosomal receptors, a new direction for polymers in nanomedicine","volume":"11","author":"Ramirez-Garcia","year":"2023","journal-title":"J Mater Chem B."},{"issue":"Supplement_1","key":"2025102413220596300_CIT0056","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1093\/jcag\/gwac036.206","article-title":"A206 synergistic effects of histamine and proteases in visceral hypersensitivity","volume":"6","author":"Gilmour","year":"2023","journal-title":"J Can Assoc Gastroenterol."},{"issue":"Supplement_1","key":"2025102413220596300_CIT0057","doi-asserted-by":"publisher","first-page":"i22","DOI":"10.1093\/jcag\/gwae059.053","article-title":"A53 novel protease\u2013histamine interactions potentiate pain signaling evoked by fecal supernatants from IBS patients","volume":"8","author":"Jimenez Vargas","year":"2025","journal-title":"J Can Assoc Gastroenterol."},{"issue":"8","key":"2025102413220596300_CIT0058","doi-asserted-by":"publisher","first-page":"4062","DOI":"10.4049\/jimmunol.0903002","article-title":"Metabolic shifts in immunity and inflammation","volume":"184","author":"Kominsky","year":"2010","journal-title":"J Immunol."},{"key":"2025102413220596300_CIT0059","doi-asserted-by":"publisher","first-page":"1218297","DOI":"10.1155\/2018\/1218297","article-title":"Unravelling the interplay between extracellular acidosis and immune cells","volume":"2018","author":"Erra D\u00edaz","year":"2018","journal-title":"Mediators Inflamm."},{"issue":"1","key":"2025102413220596300_CIT0060","doi-asserted-by":"publisher","first-page":"18599","DOI":"10.1038\/s41598-020-75509-4","article-title":"A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors","volume":"10","author":"Baamonde","year":"2020","journal-title":"Sci Rep."},{"issue":"11","key":"2025102413220596300_CIT0061","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1097\/j.pain.0000000000001328","article-title":"Analgesic effects of a novel pH-dependent \u03bc-opioid receptor agonist in models of neuropathic and abdominal pain","volume":"159","author":"Rodriguez-Gaztelumendi","year":"2018","journal-title":"Pain."},{"issue":"6328","key":"2025102413220596300_CIT0062","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1126\/science.aai8636","article-title":"A nontoxic pain killer designed by modeling of pathological receptor conformations","volume":"355","author":"Spahn","year":"2017","journal-title":"Science."},{"issue":"1","key":"2025102413220596300_CIT0063","doi-asserted-by":"crossref","first-page":"15172","DOI":"10.1038\/s41598-022-19568-9","article-title":"Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP","volume":"12","author":"Celik","year":"2022","journal-title":"Sci Rep."},{"issue":"4","key":"2025102413220596300_CIT0064","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1136\/gutjnl-2021-324070","article-title":"Agonist that activates the \u00b5-opioid receptor in acidified microenvironments inhibits colitis pain without side effects","volume":"71","author":"Jim\u00e9nez-Vargas","year":"2022","journal-title":"Gut."},{"issue":"11","key":"2025102413220596300_CIT0065","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1097\/j.pain.0000000000002956","article-title":"Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid","volume":"164","author":"Degro","year":"2023","journal-title":"Pain."},{"issue":"3","key":"2025102413220596300_CIT0066","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1111\/bph.17363","article-title":"A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation","volume":"182","author":"Degro","year":"2025","journal-title":"Br J Pharmacol."},{"issue":"24","key":"2025102413220596300_CIT0067","doi-asserted-by":"publisher","first-page":"4158","DOI":"10.1016\/j.bpj.2024.07.007","article-title":"Effects of pH on opioid receptor activation and implications for drug design","volume":"123","author":"Stein","year":"2024","journal-title":"Biophys J."},{"issue":"1","key":"2025102413220596300_CIT0068","doi-asserted-by":"publisher","first-page":"19344","DOI":"10.1038\/s41598-019-55886-1","article-title":"pK(a) of opioid ligands as a discriminating factor for side effects","volume":"9","author":"Del Vecchio","year":"2019","journal-title":"Sci Rep."},{"issue":"1","key":"2025102413220596300_CIT0069","doi-asserted-by":"publisher","first-page":"8965","DOI":"10.1038\/s41598-018-27313-4","article-title":"Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist","volume":"8","author":"Spahn","year":"2018","journal-title":"Sci Rep."},{"key":"2025102413220596300_CIT0070","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fphar.2013.00123","article-title":"Targeting pain and inflammation by peripherally acting opioids","volume":"4","author":"Stein","year":"2013","journal-title":"Front Pharmacol."}],"container-title":["Journal of the Canadian Association of Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcag\/article-pdf\/8\/5\/152\/63782798\/gwaf016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcag\/article-pdf\/8\/5\/152\/63782798\/gwaf016.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T17:22:14Z","timestamp":1761326534000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcag\/article\/8\/5\/152\/8204275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":70,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jcag\/gwaf016","relation":{},"ISSN":["2515-2084","2515-2092"],"issn-type":[{"value":"2515-2084","type":"print"},{"value":"2515-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,7,17]]}}}