Blaise M Costa, De'Yana Hines, Nakia Phillip, Seth C Boehringer, Ramu Anandakrishnan, McAlister Council-Troche, Jennifer L Davis
{"title":"Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator.","authors":"Blaise M Costa, De'Yana Hines, Nakia Phillip, Seth C Boehringer, Ramu Anandakrishnan, McAlister Council-Troche, Jennifer L Davis","doi":"10.1016/j.jpet.2025.103401","DOIUrl":"10.1016/j.jpet.2025.103401","url":null,"abstract":"<p><p>N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103401"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630343","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":"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 (CCl<sub>4</sub>)-induced liver fibrosis in mice through M1 polarization. C57BL/6 mice were intraperitoneally injected with CCl<sub>4</sub> twice weekly to induce liver fibrosis. Male mice were randomly divided into 4 groups (n = 5): the oil group, the CCl<sub>4</sub> group, the low-dose KA-treatment CCl<sub>4</sub> group (50 mg/kg/day KA), and the high-dose KA-treatment CCl<sub>4</sub> 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":"2025-04-01","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":"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":"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":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060161/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leen H Kawas, Brent J Yamamoto, John W Wright, Joseph W Harding
{"title":"Retraction notice to \"Mimics of the Dimerization Domain of Hepatocyte Growth Factor Exhibit Anti-Met and Anticancer Activity\" [J Pharmacol Exp Ther 339 (2011) 509-518].","authors":"Leen H Kawas, Brent J Yamamoto, John W Wright, Joseph W Harding","doi":"10.1016/j.jpet.2025.103568","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103568","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103568"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988511","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}
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
{"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":"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 EC<sub>50</sub> of 41 nM and 17 nM in cell-based functional inositol 1-phosphate-ELISA assay and Ca<sup>2+</sup> 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":"2025-04-01","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}
Caroline C Benoist, Leen H Kawas, Mingyan Zhu, Katherine A Tyson, Lori Stillmaker, Suzanne M Appleyard, John W Wright, Gary A Wayman, Joseph W Harding
{"title":"Retraction notice to \"The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System\" [J Pharmacol Exp Ther 351 (2014) 390-402].","authors":"Caroline C Benoist, Leen H Kawas, Mingyan Zhu, Katherine A Tyson, Lori Stillmaker, Suzanne M Appleyard, John W Wright, Gary A Wayman, Joseph W Harding","doi":"10.1016/j.jpet.2025.103567","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103567","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103567"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999902","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}
Eric R Goedken, Zhi Su, Alex Lipovsky, Arun Kannan, Katharine L Chu, Samantha Ciura, Sage E Foley, Kristine E Frank, Christian A Goess, Sujatha Gopalakrishnan, Stephen N Greszler, Hasan A Khan, Laura J Leys, Jacob J King, Suzanne L Mathieu, Sanjay C Panchal, Stephanie Paulsboe, Matt Perham, Ashley L Ramos, Peter F Slivka, Myron Srikumaran, Matthew P Webster, Emma L Wambeke, Haizhong Zhu, Victoria E Scott, Steve McGaraughty, Prisca Honore
{"title":"Small molecule interleukin (IL) 17A/A antagonists and antibodies blocking both IL17A/A and IL17A/F demonstrate equivalent degrees of efficacy in preclinical models of skin and joint inflammation.","authors":"Eric R Goedken, Zhi Su, Alex Lipovsky, Arun Kannan, Katharine L Chu, Samantha Ciura, Sage E Foley, Kristine E Frank, Christian A Goess, Sujatha Gopalakrishnan, Stephen N Greszler, Hasan A Khan, Laura J Leys, Jacob J King, Suzanne L Mathieu, Sanjay C Panchal, Stephanie Paulsboe, Matt Perham, Ashley L Ramos, Peter F Slivka, Myron Srikumaran, Matthew P Webster, Emma L Wambeke, Haizhong Zhu, Victoria E Scott, Steve McGaraughty, Prisca Honore","doi":"10.1016/j.jpet.2025.103525","DOIUrl":"10.1016/j.jpet.2025.103525","url":null,"abstract":"<p><p>T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well as the heterodimeric IL17A/F isoform, all having well known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such as secukinumab and ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and are under further investigation as therapies in inflammatory disorders such as hidradenitis suppurativa and giant cell arteritis. Because many patients dislike injections with needles, orally bioavailable small molecule IL17 antagonists are desirable as next-generation drugs as long as they can replicate the degree of efficacy observed with anti-IL17A biologics. We recently described novel small molecules binding as 2 copies to the IL17A/A homodimer with only weak effects on the IL17A/F heterodimer. Because approved antibodies binding IL17A neutralize both IL17A/A and IL17A/F, we assessed whether targeting IL17A/A would be sufficient to bring efficacy comparable to IL17A biologics. In comparison to IL17A/F and IL17F/F, we found that the IL17A/A homodimer is the strongest initiator of signaling and that comparable IL17A/A to IL17A/F ratios are expressed in Th17 cells and in human psoriatic skin tissue. Furthermore, our IL17A/A-specific small molecules block the effects of Th17 cell supernatants on keratinocytes to similar maximal responses as anti-IL17A. Our IL17A/A-selective antagonists deliver comparable efficacy to anti-IL17A biologics in several rodent inflammatory models of psoriasiform dermatitis and arthritis. These results support neutralizing IL17A/A with oral small molecule antagonists is an attractive approach to provide differentiated, next-generation therapies for inflammatory disorders. SIGNIFICANCE STATEMENT: This study found that orally active small molecule antagonists of the proinflammatory cytokine IL17A that preferentially bind the IL17A/A form produced equivalent efficacy to monoclonal antibodies that can neutralize both IL17A/A and IL17A/F. This indicates that the IL17A/A homodimer is the dominant isoform driving inflammation in diseases such as psoriasis and that oral inhibitors targeting IL17A/A may be useful next-generation IL17 therapeutics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103525"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699565","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":"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 A<sub>2</sub> (TxA<sub>2</sub>) generation, it suggests the important role of tipifarnib on TxA<sub>2</sub> generation in platelets. Consistently, tipifarnib did not affect the 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA<sub>2</sub> 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 TxA<sub>2</sub> generation, were partially inhibited by tipifarnib. Importantly, the ELISA assay showed that 2-MeSADP- and AYPGKF-induced TxA<sub>2</sub> generation was significantly inhibited in the presence of tipifarnib, confirming the role of tipifarnib on TxA<sub>2</sub> 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 TxA<sub>2</sub> generation. Tipifarnib plays a role in platelet function by regulating TxA<sub>2</sub> 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 A<sub>2</sub> 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":"2025-04-01","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}
Ayaz Shahid, Steven Yeung, Rita Miwalian, Angela Mercado, Bradley T Andresen, Ying Huang
{"title":"Retraction notice to \"Mitigation of Nitrogen Mustard-Induced Skin Injury by the β-Blocker Carvedilol and Its Enantiomers\" [J Pharmacol Exp Ther 388 (2024) 495-505].","authors":"Ayaz Shahid, Steven Yeung, Rita Miwalian, Angela Mercado, Bradley T Andresen, Ying Huang","doi":"10.1016/j.jpet.2025.103569","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103569","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103569"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006180","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}
Deepa Reddy, Zhucheng Lin, Sujay Ramanathan, Xuan Luo, Richa Pande, Yuzhen Tian, Christine M Side, Jacqueline M Barker, Ahmet Sacan, Julie A Blendy, Seena K Ajit
{"title":"Morphine-induced hyperalgesia impacts small extracellular vesicle microRNA composition and function.","authors":"Deepa Reddy, Zhucheng Lin, Sujay Ramanathan, Xuan Luo, Richa Pande, Yuzhen Tian, Christine M Side, Jacqueline M Barker, Ahmet Sacan, Julie A Blendy, Seena K Ajit","doi":"10.1016/j.jpet.2025.103398","DOIUrl":"10.1016/j.jpet.2025.103398","url":null,"abstract":"<p><p>Morphine and other synthetic opioids are widely prescribed to treat pain. Prolonged morphine exposure can paradoxically enhance pain sensitivity in humans and nociceptive behavior in rodents. To better understand the molecular mechanisms underlying opioid-induced hyperalgesia, we investigated changes in microRNA (miRNA) composition of small extracellular vesicles (sEVs) from the serum of mice after a morphine treatment paradigm that induces hyperalgesia. We observed significant differential expression of 18 miRNAs in sEVs from morphine-treated mice of both sexes compared with controls. Several of these miRNAs were bioinformatically predicted to regulate cyclic AMP response element binding protein (CREB), a well characterized transcription factor implicated in pain and drug addiction. We confirmed the binding and repression of Creb mRNA by miR-155 and miR-10a. We tested if serum-derived sEVs from morphine-treated mice could elicit nociceptive behavior in naïve recipient mice. Intrathecal injection of 1 μg sEVs did not significantly impact basal mechanical and thermal thresholds in naïve recipient mice. However, prophylactic 1 μg sEV administration in recipient mice resulted in faster resolution of complete Freund's adjuvant-induced mechanical and thermal inflammatory hypersensitivity. Other behaviors assayed following administration of these sEVs were not impacted, including sEV-conditioned place preference and locomotor sensitization. These results indicate that morphine regulation of serum sEV composition can contribute to analgesia and suggest a potential for sEVs to be a nonopioid therapeutic intervention strategy to treat pain. SIGNIFICANCE STATEMENT: A mouse model of opioid-induced hyperalgesia was used to show that chronic morphine treatment causes differential microRNA packaging into small extracellular vesicles (sEVs) present in the serum of mice. Two of these sEV microRNAs can downregulate CREB expression, and administration of these sEVs attenuates pain hypersensitivity in recipient mice. These studies position sEVs as a potential pain therapeutic and highlight changes underlying opioid-induced hyperalgesia, shedding light on a phenomenon with unclear pathophysiology.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103398"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}