Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Regulation of glucocorticoid receptor nuclear localization in prostate cancer cells.","authors":"Guang Chen, Shidong Lv, Laura E Pascal, Zhou Wang","doi":"10.1016/j.jpet.2025.103577","DOIUrl":"10.1016/j.jpet.2025.103577","url":null,"abstract":"<p><p>Glucocorticoid receptor (GR) plays important roles in many diseases including prostate cancer. Intracellular shuttling of GR is thought to be an important mechanism regulating its localization to the nucleus required for transactivation of GR target genes. Here, using fluorescent microscopy coupled with pulse-chase and nucleocytoplasmic fractionation coupled with western blot, we provided evidence that GR can be imported and then degraded in the nucleus in the absence of ligand. We also showed that nuclear GR was stabilized by glucocorticoid hormone and that hormone withdrawal caused nuclear GR degradation, but not export. Further analysis showed that GR ubiquitination occurred predominantly in the nucleus compared with cytoplasm and was suppressed by glucocorticoids. Using small interfering RNA knockdown, we showed that loss of E3 ligase CHIP significantly inhibited GR ubiquitination and degradation in the nucleus, while enhancing the expression of GR target gene SGK1. These findings support an updated model that GR nucleocytoplasmic trafficking is a 1-way trip, involving nuclear import but not export. Future studies should focus on defining the mechanisms regulating GR ubiquitination and degradation in the nucleus, which may lead to novel approaches to modulate GR function for disease treatment. SIGNIFICANCE STATEMENT: This study suggests that glucocorticoid receptor (GR) nucleocytoplasmic trafficking is a 1-way trip, involving nuclear import but not export. This will guide future studies on defining the mechanisms regulating GR nuclear localization, which may lead to novel approaches to modulate GR function for disease treatment.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103577"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017799","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":"Acquired resistance to jadomycin B in human triple-negative breast cancer cells is associated with increased cyclooxygenase-2 expression.","authors":"Brendan T McKeown, Brandon Groves, David L Jakeman, Kerry B Goralski","doi":"10.1016/j.jpet.2025.103565","DOIUrl":"10.1016/j.jpet.2025.103565","url":null,"abstract":"<p><p>Jadomycin B, produced by the soil bacterium Streptomyces venezuelae ISP5230, induces cytotoxicity in human breast cancer cells in vitro and has antitumoral effects in animal models. In models of multidrug-resistant, triple-negative breast cancer, jadomycin B has shown promise as it is not a substrate of ABCB1 and ABCG2 drug efflux transporters. The generation of reactive oxygen species and inhibition of topoisomerases are potential mechanisms of jadomycin B-mediated DNA damage and apoptosis. However, the mechanisms of jadomycin B's anticancer activity have not been fully elucidated. By gradually exposing MDA-MB-231 triple-negative human breast cancer cells to jadomycin B, we hypothesized that resistance could be selected to further understand jadomycin B's pharmacological mechanisms. A 3-fold increase in the jadomycin B IC₅₀ was observed in MDA-MB-231 cells exposed to increasing jadomycin B concentrations (0-3 μM) over 7 months, herein 231-JB cells. The 231-JB cells were cross-resistant to jadomycin F and S but not to the comparator drugs mitoxantrone, doxorubicin, and SN-38. The 231-JB cells did not have increased mRNA expression of topoisomerase-2 nor ABCB1 and ABCG2. Cyclooxygenase-2 (COX-2) increased by 25-fold, but expression of prostaglandin E₂ receptor 4 did not significantly change. Cotreatment with celecoxib (15-45 μM), a COX-2 inhibitor, resensitized the 231-JB cells to jadomycin B (IC₅₀ = 1.41 ± 0.24 to 0.75 ± 0.31 μM vs 2.28 ± 0.54 with 0 μM celecoxib). To our knowledge, this work represents the first report of the involvement of COX-2 in jadomycin B activity in vitro, proving to be an exciting new target for the exploration of jadomycin B anticancer activity. SIGNIFICANCE STATEMENT: Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin production, is associated with procancer signaling. COX-2, ABCB1, and ABCG2 overexpression are typically correlated in cancer, contributing to chemotherapy resistance. We observed increased COX-2, but not ABCG2 or ABCB1, expression in 231-JB cells. This indicates that jadomycin B triggers a distinct resistance mechanism. The COX-2 inhibitor celecoxib reversed jadomycin B resistance in 231-JB cells. As such, 231-JB cells represent an important model for COX-2 signaling in breast cancer and jadomycin B mechanism of action.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103565"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030538","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":"Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.","authors":"Sreevidhya Ramakrishnan, Tanveer Singh, Albert Chen, Xin Wu, Doodipala Samba Reddy","doi":"10.1016/j.jpet.2025.103555","DOIUrl":"10.1016/j.jpet.2025.103555","url":null,"abstract":"<p><p>Children are particularly susceptible to the neurotoxic effects of organophosphates, which can lead to developmental neuronal deficits and associated dysfunction, including cognitive disabilities, epilepsy, and associated comorbidities. Anticonvulsants like benzodiazepines fail to prevent the lasting neurobehavioral and neuropathological effects of organophosphate exposure, emphasizing the need for new anticonvulsants to address these effects. This study evaluated the efficacy of the synthetic neurosteroid ganaxolone (GX) in combating persistent behavioral deficits, electrographic abnormalities, and neuropathological damage induced by diisopropylfluorophosphate (DFP) intoxication in pediatric rats. Postnatal day 21 rats were exposed to DFP acutely and were treated with GX (5-10 mg/kg). Behavior deficits were systematically monitored up to 3 months after exposure. Video electroencephalography at 3 months assessed spontaneous recurrent seizures, nonconvulsive epileptiform discharges, high-frequency oscillations, and interictal spike activity. GX treatment significantly mitigated anxiety, aggression, memory deficits, and depression-like phenotypes in DFP-exposed pediatric animals. It also reduced DFP-induced occurrence of epileptic biomarkers such as spontaneous recurrent seizures, epileptiform discharges, interictal spikes, and high-frequency oscillations demonstrating potential disease-modifying effects. Histological analysis showed that GX decreased the loss of parvalbumin (+) inhibitory neurons, neuronal nuclei antigen (+) principal neurons, and aberrant mossy fiber sprouting. GX also reduced neuroinflammation, indicated by decreased ionized calcium binding adaptor molecule 1 (+) microgliosis. Together, these results demonstrate the neuroprotective activity of GX in mitigating chronic neurologic dysfunction, neuroinflammation, and neurodegeneration and confirm GX as a promising treatment option for DFP exposure. SIGNIFICANCE STATEMENT: Acute organophosphate (OP) intoxication poses a severe risk, particularly to children, leading to life-threatening seizures and long-term neurological deficits. Current treatments, including benzodiazepines, are less effective against persistent seizures and neurological sequel after acute exposure. This study explores the potential of ganaxolone, a synthetic neurosteroid, to mitigate the neurodevelopmental consequences of OP exposure. Our findings reveal that ganaxolone provides significant neuroprotection in a pediatric model of OP intoxication, reducing long-term seizures, ictal biomarkers, neurodegeneration, neuroinflammation, and associated neurological dysfunctions, offering a promising therapeutic avenue for pediatric victims of OP exposure.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103555"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970332","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":"Sex-related disparities in coronary artery disease in postmenopausal women-a global view and recommendations for the future.","authors":"Diego Samuel Claudio Moreno, Karla Yazmín Franco Rodríguez, Rubén Alejandro León Laredo, María Fernanda Rosas Anaya, Itza Lisseth Huerta Martínez, Iñaki Leonel Salgado Rodríguez, Elia María Ortiz Colin, Luis Francisco Chávez Vázquez, Erick Alexanderson Rosas","doi":"10.1016/j.jpet.2025.103535","DOIUrl":"10.1016/j.jpet.2025.103535","url":null,"abstract":"<p><p>Postmenopausal women undergo significant hormonal changes that impact their cardiovascular health. This article explores these hormonal shifts and their implications for cardiovascular risk, alongside physiological changes, clinical implications, and management strategies. Postmenopausal women commonly experience increased incidence of hypertension, dyslipidemia, and glucose intolerance, contrasting with premenopausal profiles and contributing to increased cardiovascular risk. Recent research highlights and future directions are also discussed. This review aims to equip clinicians with the latest insights to develop effective strategies for reduced cardiovascular risk and prevent cardiovascular events and mortality in postmenopausal women. SIGNIFICANCE STATEMENT: Postmenopausal women exhibit a higher prevalence of severe coronary artery disease alongside multiple comorbidities. Nonetheless, there remains a scarcity of data for comparing risk factors, clinical features, and angiographic severity of coronary artery disease between pre- and postmenopausal women and men. Although there are known differences in the development, type, and prognosis of chronic coronary syndrome between both sexes; there are no differences in approach in the guidelines.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103535"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032061","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":"Follistatin-like protein 1: Implications for renal disease progression.","authors":"Yiqi Gao, Junyi Ren, Haoyu Peng, Moussa Ide Nasser, Chi Liu","doi":"10.1016/j.jpet.2025.103564","DOIUrl":"10.1016/j.jpet.2025.103564","url":null,"abstract":"<p><p>Renal diseases, including glomerulonephritis, acute kidney injury, chronic kidney failure, and kidney tumors are all current global health challenges. Lesions in other systems can cause renal diseases and can affect other systems or even the whole body. Despite ongoing advancements in pharmaceutical and technological innovations, the prognosis for end-stage renal disease, encompassing renal failure and tumors, continues to be bleak. Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein produced mainly by mesenchymal cells. FSTL1 is a glycoprotein that belongs to the family of secreted, cysteine-rich acidic proteins (SPARC). It plays a pivotal role in cell survival, proliferation, differentiation, and migration, as well as in modulating inflammation and immune responses. Research has shown that FSTL1 plays a crucial role in the onset and progression of renal diseases. This review explores the functions and underlying mechanisms of FSTL1 in kidney pathology. SIGNIFICANCE STATEMENT: This review highlights the pivotal role of FSTL1 in renal diseases, particularly its involvement in renal fibrosis, inflammation, and ischemia-reperfusion injury. By elucidating its dual roles across different pathologies, this work underscores FSTL1's potential as both a biomarker and a therapeutic target, offering novel insights for managing chronic kidney disease and associated complications.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103564"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041135","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":"Environmental determinants of ketamine's prohedonic and antianhedonic efficacy: Persistence of enhanced reward responsiveness is modulated by chronic stress.","authors":"Amaya R Jenkins, Daniela B Radl, Thomas J Kornecook, Diego A Pizzagalli, Jack Bergman, Derek L Buhl, Patricio O'Donnell, Brian D Kangas","doi":"10.1016/j.jpet.2025.103572","DOIUrl":"10.1016/j.jpet.2025.103572","url":null,"abstract":"<p><p>Ketamine, a dissociative anesthetic with well documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of ketamine's clinical efficacy may be its antianhedonic action. Anhedonia is an endophenotype of depression defined by decreased responsivity to previously rewarding stimuli and is generally not ameliorated by conventional antidepressants, emphasizing the need to examine underlying behavioral mechanisms of action. In this study, the probabilistic reward task, a reverse-translated assay originally designed to objectively quantify anhedonic phenotypes in human subjects, was used in rats to examine ketamine's effects on reward responsiveness under conditions without programmed stressors (3.2-32.0 mg/kg) or during ongoing chronic exposure to ecologically relevant stress (10.0 mg/kg). Results showed that under conditions without programmed stress, ketamine produced significant prohedonic effects in the probabilistic reward task, defined by increases in reward responsiveness that dissipated within 24 hours. In rats exposed to ongoing chronic stress, ketamine produced significant antianhedonic effects, defined by the rescue of blunted reward responsiveness, that persisted for nearly 1 week. Taken together, the prolonged antianhedonic effects of ketamine in rats experiencing chronic stress, compared with the shorter-lived prohedonic effects in subjects without exposure to programmed stressors, are striking and highlight the role of environmental determinants in the effects of ketamine on behavioral processes. Moreover, the translational nature of this experimental design may offer the opportunity to accelerate development of novel antianhedonic therapeutics. SIGNIFICANCE STATEMENT: Although ketamine is used for the management of treatment-resistant depression, its precise behavioral mechanisms of action are not fully delineated. Emerging evidence suggests the attenuation of anhedonia plays a key role in its rapid-acting therapeutic efficacy. To evaluate this possibility, the effects of ketamine were studied using a reverse-translated assay of reward responsiveness in rats and documented to be short-lived (prohedonic) under nonstressful conditions and persistent (antianhedonic) under stressful conditions, informing ketamine effects in healthy versus depressed individuals.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103572"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015487","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":"Histamine H1 Receptor: A potential therapeutic target for pancreatic ductal adenocarcinoma.","authors":"Cristina Salmerón, Elena Tomás Bort, Krishna Sriram, Mehrak Javadi-Paydar, Jane E Smitham, Kimberly Pham, Richard P Grose, Peter J McCormick, Anna DiNardo, Jonathan Weitz, Hervé Tiriac, Andrew M Lowy, Paul A Insel","doi":"10.1016/j.jpet.2025.103573","DOIUrl":"10.1016/j.jpet.2025.103573","url":null,"abstract":"<p><p>Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a dismal 5-year survival (∼13%). Thus, new, effective, and ideally, less toxic therapies are desperately needed. Epidemiologic studies have found that patients with PDAC prescribed H1-antihistamines have improved survival. Expression of the histamine H1 receptor (HRH1), a G protein-coupled receptor which is blocked by approved H1-antihistamines, is increased by ∼20-fold in PDAC tumors compared with normal pancreas. Here, we used bioinformatic and molecular biological techniques to identify the cellular localization of HRH1 in the PDAC tumor microenvironment, assess functional responses to HRH1 activation, and define its potential biological roles in PDAC. We found that HRH1 is primarily expressed in cancer cells of PDAC tumors in humans and KPC mice (mice engineered to develop PDAC) and signals via G protein q/11 to increase intracellular Ca²⁺. HRH1 activation increases migration and invasion by PDAC cancer cells. Orally administered fexofenadine, an H1-antihistamine, was bioavailable in the tumors of KPC mice and yielded smaller pancreatic tumor tissue weights and lower expression of immunomodulatory (interleukin 6 and PD-1) and fibrotic (Col1A1) genes than in vehicle-control KPC mice. Thus, PDAC cancer cells express HRH1, which is functional in vitro and in vivo, suggesting that the repurposing of approved H1-antihistamines may be an efficacious and safe therapeutic approach for patients with PDAC. SIGNIFICANCE STATEMENT: Pancreatic ductal adenocarcinoma (PDAC) has a ∼13% 5-year survival rate, highlighting the need for new therapies. The HRH1 (histamine) receptor, associated with poorer survival, is upregulated in PDAC tumors. This study found that HRH1 is functional in PDAC cells, increasing intracellular Ca²⁺ via G_q/11 and promoting tumorigenic responses. KPC mice treated with an H1-antihistamine have reduced pancreas weight and lower proinflammatory and fibrotic markers in PDAC tumors. Thus, HRH1 may be a potential target for repurposing approved H1-antihistamines to treat PDAC.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103573"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024347","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":"Next-generation of antithrombotic therapies: Beyond conventional drugs.","authors":"Wei Li, Hong Yue","doi":"10.1016/j.jpet.2025.103574","DOIUrl":"10.1016/j.jpet.2025.103574","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103574"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024348","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":"Association between duration, initiation time, routes, and formulations of menopausal hormone therapy use and Alzheimer disease in women: A systematic review and meta-analysis.","authors":"Qixiang Song, Qi Wang, Dang Wu, Zhe Zhang, Mengyao Chen, Chunying Fu, Meiling Li, Xiaoyi Wang, Yanqing Zhao, Dongshan Zhu","doi":"10.1016/j.jpet.2025.103554","DOIUrl":"10.1016/j.jpet.2025.103554","url":null,"abstract":"<p><p>The purpose of this study was to investigate the effect of menopausal hormone therapy (MHT) on the risk of Alzheimer disease (AD) by examining its duration, initiation time, routes of administration, and formulations through systematic review and meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched on March 15, 2023. We selected cohort studies, case-control studies, and randomized controlled trials on the effect of MHT on AD in women. Odds ratio, relative risk, and hazard ratio were extracted. Random-effect models were used to estimate the polled estimates (relative risk [RR] or odds ratio [OR]) and their 95% confidence interval (95% CI). We included 3 randomized controlled trials, 12 cohort studies, and 16 case-control studies. A total of 7,710,379 women were included. Pooled estimates showed that MHT use for 3-5 years (cohort, RR = 0.56, 95% CI: 0.34-0.93) or initiation within 5 years of menopause (cohort, RR = 0.70, 95% CI: 0.49-0.99) reduced the risk of AD. Oral administration reduced AD risk (cohort, RR = 0.42, 95% CI: 0.40-0.44). Combining estrogen and progesterone (case-control, OR = 1.13, 95% CI: 1.05-1.21) or progesterone only (case-control, OR = 1.13, 95% CI: 1.10-1.17) increases AD risk. Tibolone increased AD risk (cohort, RR = 1.04, 95% CI: 1.01-1.07; case-control, OR = 1.07, 95% CI: 1.01-1.14). MHT-protected apolipoprotein E genotype 4 carriers (cohort, RR = 0.13, 95% CI: 0.02-0.90), depressed populations (cohort, RR = 0.85, 95% CI: 0.80-0.90), and Americas (cohort, RR = 0.54, 95% CI: 0.37-0.80; case-control, OR = 0.68, 95% CI: 0.47-0.99) from AD. Using MHT early (within 5 years after menopause) for about 5 years may protect against AD. However, combining estrogen with progesterone, or using progesterone only, could increase AD risk. Oral MHT methods are more effective than transdermal ones in reducing this risk. SIGNIFICANCE STATEMENT: Menopausal hormone therapy (MHT) use within 5 years after menopause could offer protective benefits against Alzheimer disease (AD). A combination of estrogen and progesterone, using progesterone only or tibolone usage was connected with an elevated risk of AD. Oral MHT was more effective than transdermal methods in lowering AD risk. MHT lowered AD risk in apolipoprotein E genotype 4 allele carriers, individuals with depression, and Americans. MHT regimens should be highly personalized.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103554"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970775","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":"The calcium channel agonist (±)-BAY-K-8644 attenuates the ability of gabapentinoids to increase the potency of fentanyl and heroin and decrease the potency of cocaine and d-methamphetamine to elicit discriminative stimulus effects in rats.","authors":"Takato Hiranita, Amanda K Grisham, Abram E Mijares, Nicholas P Ho, Charles P France","doi":"10.1016/j.jpet.2025.103523","DOIUrl":"10.1016/j.jpet.2025.103523","url":null,"abstract":"<p><p>During the opioid epidemic there has been a significant increase in the number of prescriptions for gabapentinoids (gabapentin and pregabalin), which block the α₂δ-subunit of voltage-gated calcium channels (VGCCs). In rats, gabapentinoids enhance the potency of the mu opioid receptor (MOR) agonists fentanyl and heroin and decrease the potency of the stimulant drugs cocaine and d-methamphetamine to elicit discriminative stimulus effects. Moreover, (±)-BAY-K-8644, a dihydropyridine-type agonist at the α₁-subunit of VGCCs (α₁-VGCCs), prevents the antiallodynic effects of gabapentin in rats. The mechanism(s) of interaction between gabapentinoids and MOR agonists and between gabapentinoids and stimulant drugs is/are unclear. This study tested the following hypotheses: (1) the dihydropyridine-type α₁-VGCC blocker nimodipine increases the potency of MOR agonists to elicit discriminative stimulus effects; and (2) (±)-BAY-K-8644 attenuates the ability of gabapentinoids and nimodipine to increase the potency of MOR agonists to elicit discriminative stimulus effects. In rats trained to discriminate fentanyl (0.0032 mg/kg) or cocaine (3.2 mg/kg) from saline, neither (±)-BAY-K-8644 nor nimodipine elicited significant fentanyl- or cocaine-appropriate responding. (±)-BAY-K-8644 did not significantly alter discrimination dose-effect functions of MOR agonists or stimulant drugs whereas nimodipine dose-dependently shifted the MOR agonist discrimination dose-effect functions to the left and the stimulant drug discrimination dose-effect functions to the right. (±)-BAY-K-8644 dose-dependently attenuated the ability of nimodipine and gabapentinoids to increase the potency of MOR agonists and decrease the potency of stimulant drugs to elicit discriminative stimulus effects. These results suggest that gabapentinoids alter the potency of MOR agonists and stimulant drugs to elicit discriminative stimulus effects via blockade of α₁-VGCCs. SIGNIFICANCE STATEMENT: Prescriptions for gabapentinoids (gabapentin and pregabalin) increased significantly during the opioid epidemic. Using (±)-BAY-K-8644, a dihydropyridine-type agonist at the α₁-subunit of the voltage-gated calcium channel (α₁-VGCC), this study reports that in male and female rats, gabapentinoids increase the potency of fentanyl and heroin and decrease the potency of cocaine and d-methamphetamine to elicit discriminative stimulus effects via blockade of dihydropyridine-binding sites on α₁-VGCC. These results suggest that actions of drugs at α₁-VGCCs contribute to the opioid epidemic and opioid/stimulant co-use.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 5","pages":"103523"},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989074","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}