Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Commentary: Behavior as an important determinant of drug action.","authors":"James E Barrett, Alice M Young, Linda Dykstra","doi":"10.1016/j.jpet.2025.103528","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103528","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103528"},"PeriodicalIF":3.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of ZYDG2: a potent, selective, and safe GPR40 agonist for treatment of type 2 diabetes.","authors":"Mukul R Jain, Suresh R Giri, Chitrang J Trivedi, Bibhuti B Bhoi, Akshyaya Chandan Rath, Rohan M Rathod, Rajesh Sundar, Debdutta Bandyopadhyay, Rashmi Ramdhave, Gautam D Patel, Brijesh Kumar Srivastava, Ranjit C Desai","doi":"10.1016/j.jpet.2025.103534","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103534","url":null,"abstract":"<p><p>GPR40/FFA1 receptor, predominantly expressed in pancreatic β-cells, mediates glucose-stimulated insulin secretion by free fatty acids. Fasiglifam-GPR40 agonist was terminated in phase III clinical trials due to adverse liver effects. ZYDG2 is identified as a novel, potent and selective agonist for GPR40, exhibiting EC₅₀ of 41 nM and 17 nM in cell-based functional inositol 1-phosphate-ELISA assay and Ca²⁺ mobilization assay, respectively. ZYDG2 has demonstrated dose-dependent improvement in glucose tolerance tests and increased insulin secretion in neonatal streptozotocin Wistar rats. After repeated dose administration for 15 weeks, ZYDG2 showed efficacy without tachyphylaxis. ZYDG2 significantly increased the glucose infusion rate in a hyperglycemic clamp study and demonstrated antidiabetic efficacy in mice models of type 2 diabetes mellitus, which was not reported for fasiglifam. ZYDG2 exhibited 60%-100% oral bioavailability across preclinical species, including mice, rats, dogs, and primates. Liver toxicity of fasiglifam was associated with its bile acid transporter inhibition, whereas ZYDG2 showed no inhibition (up to 300 μM). In rat acute toxicity studies, the maximum tolerated dose for ZYDG2 was 2000 mg/kg, whereas fasiglifam was tolerable up to 300 mg/kg. Fasiglifam treatment at 300 mg/kg for 10 days in rats caused a significant rise in serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin level along with vacuolation, ulceration, and red foci in liver tissue, whereas ZYDG2 showed no liver toxicity up to 300 mg/kg. Moreover, after 28 days of repeated dose treatment of ZYDG2, the no-observed-adverse-effect-level was found to be 300 mg/kg. This robust data conclusively demonstrates that ZYDG2 is a highly promising and unequivocally safe therapeutic candidate for the treatment of type 2 diabetes. SIGNIFICANCE STATEMENT: ZYDG2 is a potent, selective, and safe GPR40 agonist which may be a promising candidate for the treatment of type 2 diabetes as it has shown better efficacy and safety profile compared with fasiglifam.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103534"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects and molecular mechanisms of farnesyltransferase inhibitor tipifarnib on platelet activation.","authors":"Preeti K Chaudhary, Sanggu Kim, Soochong Kim","doi":"10.1016/j.jpet.2025.103530","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103530","url":null,"abstract":"<p><p>Tipifarnib, a farnesyltransferase inhibitor, substantially protects against cardiovascular diseases and is currently undergoing clinical trials to treat various cancers. Platelets have a well-recognized role in the progression of cancer-associated cardiovascular diseases. Nevertheless, the effect of tipifarnib on platelet function has not been studied thus far. Thus, we investigated the effect of tipifarnib and its molecular basis on the regulation of platelet activation. 2-Methylthioadenosine diphosphate (2-MeSADP)-induced secondary waves of aggregation and dense granule secretion in murine-washed platelets were completely inhibited by tipifarnib. Since 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A₂ (TxA₂) generation, it suggests the important role of tipifarnib on TxA₂ generation in platelets. Consistently, tipifarnib did not affect the 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA₂ generation was blocked. In addition, platelet aggregation and secretion induced by low concentrations of AYPGKF and thrombin, which are affected by the positive feedback effect of TxA₂ generation, were partially inhibited by tipifarnib. Importantly, the ELISA assay showed that 2-MeSADP- and AYPGKF-induced TxA₂ generation was significantly inhibited in the presence of tipifarnib, confirming the role of tipifarnib on TxA₂ generation. Finally, tipifarnib significantly inhibited 2-MeSADP-induced protein kinase B and extracellular signal-regulated kinases phosphorylation only in nonaspirinated platelets but not in aspirinated platelets, indicating the contribution of TxA₂ generation. Tipifarnib plays a role in platelet function by regulating TxA₂ generation, thereby indicating the possibility of using tipifarnib as a single key to treat various patients with cancer with thromboembolic complications in the future. SIGNIFICANCE STATEMENT: Farnesyltransferase inhibitor tipifarnib regulates platelet activity by inhibiting thromboxane A₂ generation through the modulation of protein kinase B and extracellular signal-regulated kinase phosphorylation. Given the dual role of platelets in both thrombosis and cancer progression, tipifarnib's ability to modulate these pathways highlights its potential as a therapeutic agent in preventing thromboembolic complications in patients with cancer.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103530"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coculture of mesenchymal stem cells and macrophage: A narrative review.","authors":"Jun Ning, Rajiv Kumar Sah, Jing Wang","doi":"10.1016/j.jpet.2025.103531","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103531","url":null,"abstract":"<p><p>Stem cell transplantation is a promising treatment for repairing damaged tissues, but challenges like immune rejection and ethical concerns remain. Mesenchymal stem cells (MSCs) offer high differentiation potential and immune regulatory activity, showing promise in treating diseases such as gynecological, neurological, and kidney disorders. With scientific progress, MSC applications are overcoming traditional treatment limitations. In MSCs-macrophage coculture, MSCs transform macrophages into anti-inflammatory M2 macrophages, reducing inflammation, whereas macrophages enhance MSCs osteogenic differentiation. This coculture is vital for immune modulation and tissue repair, with models varying by contact type and dimensional arrangements. Factors such as coculture techniques and cell ratios influence outcomes. Benefits include improved heart function, wound healing, reduced lung inflammation, and accelerated bone repair. Challenges include optimizing coculture conditions. This study reviews the methodologies, factors, and mechanisms of MSC-macrophage coculture, providing a foundation for tissue engineering applications. SIGNIFICANCE STATEMENT: This review underlines the significant role of mesenchymal stem cell-macrophage coculture, providing a foundation for tissue engineering application.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103531"},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol attenuates macrophage M1 polarization and liver fibrosis by inhibiting mitogen-activated protein kinase/nuclear factor κB signaling pathway.","authors":"Jiajia Chen, Huanle Liu, Yanfang Fu, Xiaolan Chen, Shiqin Zhang, Yongqi Yang, Shengwen Li, Guixiang Wang, Tian Lan","doi":"10.1016/j.jpet.2025.103533","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103533","url":null,"abstract":"<p><p>Chronic liver inflammation is a major cause of death in patients with liver fibrosis and cirrhosis, which pose a serious health threat worldwide, and there is no effective anti-hepatic fibrosis drug. Kaempferol (KA), a flavonoid polyphenol extracted from many edible plants and traditional Chinese medicine, has been reported to possess anti-inflammatory, antioxidant, and antitumor activities and has an ameliorating effect on liver fibrosis or other fibroproliferative diseases. However, the specific regulatory mechanism of KA-reversed macrophage M1 polarization is still obscure. This study aimed to investigate the protective effects of KA on carbon tetrachloride (CCl₄)-induced liver fibrosis in mice through M1 polarization. C57BL/6 mice were intraperitoneally injected with CCl₄ twice weekly to induce liver fibrosis. Male mice were randomly divided into 4 groups (n = 5): the oil group, the CCl₄ group, the low-dose KA-treatment CCl₄ group (50 mg/kg/day KA), and the high-dose KA-treatment CCl₄ group (100 mg/kg/day KA). An equal amount of solvent was given to each group by intraperitoneal injection. The results indicated that KA decreased liver pathologic changes, hepatic macrophage recruitment, and serum alanine aminotransferase levels. Notably, it reduced the activation of M1-type macrophages in the liver. The expression of proinflammatory cytokines and genes associated with M1 macrophages, such as tumor necrosis factor-α, interleukin-6, interleukin-1β, and inducible nitric oxide synthase, was also decreased. The core targets, signaling pathways, and possible mechanisms related to the M1 polarization of KA were analyzed by network pharmacology and molecular docking. Further analysis revealed that KA regulated mitogen-activated protein kinase (MAPK)/nuclear factor κB (NF-κB) signaling pathways. Finally, the results indicated that KA regulates M1 macrophage activation by modulating the MAPK/NF-κB signaling pathways. This study revealed that KA ameliorated liver injury, inflammation, and fibrosis by inhibiting macrophage M1 polarization through the MAPK/NF-κB signaling pathway, highlighting KA as a potential novel agent for the prevention and treatment of liver fibrosis. SIGNIFICANCE STATEMENT: Chronic liver inflammation is a leading cause of mortality in patients with liver fibrosis and cirrhosis, presenting a significant global health threat. Kaempferol, as a traditional Chinese medicine, effectively suppresses M1 polarization of macrophages through the mitogen-activated protein kinase/nuclear factor κB signaling pathway, thereby ameliorating liver injury, inflammation, and fibrosis. These findings underscore the potential of kaempferol as an innovative therapeutic agent for the prevention and treatment of liver fibrosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103533"},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bazedoxifene plus conjugated estrogen to treat menopausal depression-A pilot study.","authors":"Jayashri Kulkarni, Eveline Mu, Qi Li, Marta Malicka, Emorfia Gavrilidis, Anthony de Castella, Caroline Gurvich","doi":"10.1016/j.jpet.2025.103527","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103527","url":null,"abstract":"<p><p>Gonadal hormone fluctuations in the menopausal transition, particularly the decline in brain estrogen levels, significantly contribute to menopausal depression. Although hormone replacement therapy, known as \"menopause hormone therapy,\" effectively manages physical symptoms, it is not routinely used for mental health disturbances due to limited large-scale clinical trial evidence comparing menopause hormone therapy with standard antidepressants. The recognition of menopausal mental illness as being different to major depressive disorder is currently lacking in research and clinical practice. Furthermore, concerns about the long-term safety of estrogen and progestins have prompted the exploration of alternative hormone therapies. Bazedoxifene, a selective estrogen receptor modulator, in combination with conjugated estrogens, is a newer, safe option for physical menopause symptoms. Our 12-week double-blind, randomized, placebo-controlled pilot study evaluated the effects of this combined hormone therapy on menopausal depression in 37 women. Twenty participants received bazedoxifene plus conjugated estrogen, and 17 received placebo. Results indicated that both groups had a decrease in the standard depression rating scale (Montgomery-Asberg Depression Rating Scale) scores from baseline to week 12. However, the decrease was not significantly different between groups. When we used our specific menopause depression rating scale-the Meno-D-we found that women receiving bazedoxifene plus conjugated estrogen improved significantly more compared with women taking the placebo. This suggests that the combined hormone therapy effectively targets the unique symptoms that constitute menopausal depression. Further research is needed to develop targeted treatments for menopausal depression, which appears to be a different type of depression that responds to hormone therapy. SIGNIFICANCE STATEMENT: This pilot study demonstrates that combined hormone therapy with bazedoxifene plus conjugated estrogen significantly improves symptoms of menopausal depression, a condition distinct from major depressive disorder. These findings highlight the potential of targeted hormone treatments for menopausal mental health, warranting further research to develop effective therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103527"},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopause-related changes in vascular signaling by sex hormones.","authors":"Tao Li, Zachary E Thoen, Jessica M Applebaum, Raouf A Khalil","doi":"10.1016/j.jpet.2025.103526","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103526","url":null,"abstract":"<p><p>Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103526"},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cAMP response element-binding protein: A credible cancer drug target.","authors":"Jinghui Hong, Yuheng Wu, Mengxin Li, Ki-Fong Man, Dong Song, Siang-Boon Koh","doi":"10.1016/j.jpet.2025.103529","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103529","url":null,"abstract":"<p><p>Despite advancements in radiotherapy, chemotherapy, endocrine therapy, targeted therapy, and immunotherapy, resistance to therapy remains a pervasive challenge in oncology, in part owing to tumor heterogeneity. Identifying new therapeutic targets is key to addressing this challenge because it can both diversify and enhance existing treatment options, particularly through combination regimens. The cAMP response element-binding protein (CREB) is a transcription factor involved in various biological processes. It is aberrantly activated in several aggressive cancer types, including breast cancer. Clinically, high CREB expression is associated with increased breast tumor aggressiveness and poor prognosis. Functionally, CREB promotes breast cancer cell proliferation, survival, invasion, metastasis, as well as therapy resistance by deregulating genes related to apoptosis, cell cycle, and metabolism. Targeting CREB with small molecule inhibitors has demonstrated promise in preclinical studies. This review summarizes the current understanding of CREB mechanisms and their potential as a therapeutic target. SIGNIFICANCE STATEMENT: cAMP response element-binding protein (CREB) is a master regulator of multiple biological processes, including neurodevelopment, metabolic regulation, and immune response. CREB is a putative proto-oncogene in breast cancer that regulates the cell cycle, apoptosis, and cellular migration. Preclinical development of CREB-targeting small molecules is underway.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103529"},"PeriodicalIF":3.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.","authors":"Ziqi Chen, Hekang Ding, Yunlong Zhu, Shuai Sun, Zhenyu Song, Li Zhang, Chaozhao Liang, Lingfan Xu","doi":"10.1016/j.jpet.2024.100530","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100530","url":null,"abstract":"<p><p>MicroRNAs play a crucial role in regulating tumor progression and invasion. Nevertheless, the expression of miRNA-335 in prostate cancer (PCa) and its clinical significance remain unelucidated. Here, we report that miRNA-335 functions as a tumor suppressor by regulating expression of glutaminase 1 (GLS1), a key enzyme of glutamine metabolism pathway, in PCa. In this study, we show that the expression of miRNA-335 is downregulated in PCa tissues. The level of miRNA-335 is even lower in highly invasive PCa cell lines. Furthermore, enhancing the expression of miRNA-335 inhibits PCa cell migration and invasion in vitro. Additionally, we identify GLS1 as the downstream effector, governed by miRNA-335 via 3'-untranslated region, and the direct regulation is verified by dual luciferase reporter assay. MiRNA-335 interrupts glutamine catabolism by inhibiting GLS1 enzymatic activity. Overexpression of miRNA-335 markedly suppresses tumor growth of PCa in vivo. To sum up, our results indicate that miRNA-335 acts as a tumor suppressor and has an important role in restraining the metastasis of PCa cells by targeting GLS1. These discoveries indicate that miRNA-335 could serve as a new prospective therapeutic target for PCa. SIGNIFICANCE STATEMENT: miRNA-335, a metabolism-related microRNA, is a potential therapeutic target for prostate cancer by interfering with glutaminase 1 activity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"100530"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Entourage effects of nonpsychotropic cannabinoids on visceral sensitivity in experimental colitis.","authors":"Kristofer Svendsen, Amyaouch Bradaia, Maria A Gandini, Manon Defaye, Chelsea Matisz, Nasser S Abdullah, Aaron Gruber, Gerald W Zamponi, Keith A Sharkey, Christophe Altier","doi":"10.1016/j.jpet.2025.103389","DOIUrl":"10.1016/j.jpet.2025.103389","url":null,"abstract":"<p><p>Abdominal pain is the most disabling symptom of inflammatory bowel diseases, but current treatments are limited, leading patients to seek alternatives such as cannabis. Cannabis contains over 100 cannabinoids which, unlike tetrahydrocannabinol, are biologically active compounds often without psychotropic effects (ie, nonpsychotropic cannabinoids [npCBs]). These npCBs have analgesic and anti-inflammatory properties and may show potentiating effects when administered in combination, referred to as the entourage effect. Here, we investigated the analgesic effects of cannabichromene, cannabidiol (CBD), cannabidivarin, and cannabigerol (CBG), individually and in combination, using the mouse model of dextran sulfate sodium colitis-induced visceral hypersensitivity (VHS). We then explored antinociceptive targets through patch-clamp electrophysiology on dorsal root ganglia neurons and recombinant channels. We found that a single injection of 10 mg/kg of either CBD or CBG reduced both VHS and c-Fos activation in the spinal dorsal horn. Moreover, a combination of npCBs consisting of 5 mg/kg CBD with 1 mg/kg of cannabichromene, cannabidivarin, and CBG-all at subtherapeutic dosages-reduced VHS, without altering colitis. Electrophysiological recordings revealed that the antinociceptive mixture of npCBs acts through voltage-gated sodium and calcium channels, particularly Cav2.2, but not Cav3.2 and Kv channels. These results suggest that CBD, CBG, and a mixture of npCBs given at subtherapeutic doses may be beneficial in managing VHS associated with inflammatory bowel disease. SIGNIFICANCE STATEMENT: Cannabis is increasingly used as an alternative treatment for managing pain associated with chronic conditions. Nonpsychotropic cannabinoids, such as cannabidiol, interact with ionotropic and voltage-gated ion channels. In our study, we demonstrated that cannabidiol, cannabigerol, and a combination of nonpsychotropic cannabinoids, administered at subtherapeutic doses, effectively alleviated visceral hypersensitivity associated with inflammatory bowel disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103389"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}