Neuropharmacology最新文献

{"title":"Genetic inactivation of the CRF2 receptor eliminates morphine-induced sociability deficits in female mice","authors":"Angelo Contarino","doi":"10.1016/j.neuropharm.2025.110480","DOIUrl":"10.1016/j.neuropharm.2025.110480","url":null,"abstract":"<div><div>Social behavior deficits, such as poor sociability and social isolation, are key clinical features of substance use disorders. The corticotropin-releasing factor (CRF) system may underlie the effects of substances of abuse but its implication in substance-induced social behavior deficits remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF₁ and CRF₂. Using the genetic mouse model of CRF₂ receptor-deficiency and the three-chamber task for sociability, the present studies examined the specific role for the CRF₂ receptor in sociability deficits induced by morphine. Notably, to assess possible sex-linked differences, female and male CRF₂ receptor wild-type (CRF₂ WT) or knockout (CRF₂ KO) mice were used. Intraperitoneal administration of morphine (1 mg/kg) reliably eliminated the preference for an unfamiliar same-sex conspecific over an object in female CRF₂ WT, but not in CRF₂ KO, mice, revealing a key role for the CRF₂ receptor in opiate-induced sociability deficits. In contrast, morphine almost significantly and similarly reduced the preference for an unfamiliar same-sex conspecific over an object in male CRF₂ WT and CRF₂ KO mice, indicating no role for the CRF₂ receptor. Notably, treatment with morphine never affected distance travelled during the three-chamber test, indicating that CRF₂ receptor-dependent or -independent opiate effects were specific to social behavior. The present findings provide initial evidence of a critical sex-linked role for the CRF₂ receptor in social behavior deficits induced by opiate substances, suggesting new, sex-customized, therapeutic strategy for opioid use disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110480"},"PeriodicalIF":4.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isobutyric tropine ester (Ibutropin) overcomes fentanyl-induced respiratory depression in unanesthetized rats without compromising analgesia","authors":"Paulina M. Getsy ,&nbsp;Walter J. May ,&nbsp;Alex P. Young ,&nbsp;Santhosh M. Baby ,&nbsp;Tristan H.J. Lewis ,&nbsp;Alannah McShine ,&nbsp;Samantha Massien ,&nbsp;Gregory A. Coffee ,&nbsp;James N. Bates ,&nbsp;Yee-Hsee Hsieh ,&nbsp;Stephen J. Lewis","doi":"10.1016/j.neuropharm.2025.110479","DOIUrl":"10.1016/j.neuropharm.2025.110479","url":null,"abstract":"<div><div>We are examining the pharmacological profile of tropine and tropine analogues on opioid-induced respiratory depression (OIRD). We report here the effects of Ibutropin (isobutyric tropine ester, tropine isobutyrate) on changes in ventilatory parameters, Alveolar-arterial (A-a) gradient (index of alveolar gas-exchange), arterial blood-gas (ABG) chemistry (pH, pCO₂, pO₂, sO₂), sedation (righting reflex), and antinociception (tail-flick latency) in freely-moving male Sprague Dawley rats elicited by prior injection of fentanyl. The injection of fentanyl (75 μg/kg, IV) produced (a) substantial decreases in frequency of breathing, tidal volume and minute ventilation, and changes in other ventilatory parameters, and (b) increases in A-a gradient (i.e., mismatch in alveolar ventilation-perfusion) that were accompanied by decreases in arterial blood pH, pO₂ and sO₂, and increases in pCO₂, responses consistent with reduced ventilatory drive. An injection of Ibutropin (200 μmol/kg, IV) given 5 min after fentanyl (75 μg/kg, IV) elicited an immediate and sustained reversal of the adverse effects of fentanyl on recorded ventilatory parameters, A-a gradient and ABG chemistry. Additionally, Ibutropin reduced the sedative, but not analgesic, actions of fentanyl. These findings show that Ibutropin has the profile to be advantageous for development as an agent to reverse OIRD. Since previous research has shown that tropine itself contrarily worsens the deleterious actions of fentanyl, we conclude that the positive actions of Ibutropin arise from its ability as an ester to readily enter cells and interrupt the events elicited by fentanyl in ventilatory control pathways, but not those driving the analgesic actions of fentanyl. Therefore, these findings reveal that Ibutropin has the profile to be advantageous for development as an agent to reverse OIRD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"277 ","pages":"Article 110479"},"PeriodicalIF":4.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of membrane receptors on modulating empathic pain","authors":"Guilherme Pegas Teixeira ,&nbsp;Leandro Rocha ,&nbsp;Robson Xavier Faria","doi":"10.1016/j.neuropharm.2025.110471","DOIUrl":"10.1016/j.neuropharm.2025.110471","url":null,"abstract":"<div><div>Humans can estimate each other's pain and provide adapted care to reduce it. Empathetic skills are crucial for caregivers involved in pain management; consequently, educational programs and theories have emphasized the positive role of empathy in reducing pain intensity. It is also widely assumed that if caregivers lack empathy, they will underestimate pain intensity in their patients, and this unempathetic attitude can negatively influence pain intensity perception. Empathy for pain is thought to activate the affective‒motivational components of the pain matrix, which includes the anterior insula, middle and anterior cingulate cortices and amygdala, as indicated by functional magnetic resonance imaging and other methodologies. Activity in this core neural network reflects the affective experience that activates our responses to pain and lays the neural foundation for our understanding of our own emotions and those of others. Additionally, a variety of factors can regulate the intensity of empathy for pain, such as oxytocin and vasopressin receptors. Therefore, we selectively review the molecular mechanisms by which membrane receptors modulate this pain modality.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110471"},"PeriodicalIF":4.6,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating nitazenes: A pharmacological and toxicological overview of new synthetic opioids with a 2-benzylbenzimidazole core","authors":"Marthe M. Vandeputte,&nbsp;Christophe P. Stove","doi":"10.1016/j.neuropharm.2025.110470","DOIUrl":"10.1016/j.neuropharm.2025.110470","url":null,"abstract":"<div><div>Since the first identification of isotonitazene on the recreational drug market in 2019, new synthetic opioids (NSOs) with a 2-benzylbenzimidazole core (colloquially known as ‘nitazene’ opioids) have increased in prevalence. At the end of 2024, 22 different analogues had been identified in Europe, and worrying trends indicate their increasing presence at the street level. Nitazene analogues originate from a series of research articles from the 1950–60s, but were never marketed as analgesics. Recent pharmacological research has shown that different analogues are highly active, with several being more potent than fentanyl in their ability to activate the μ-opioid receptor and produce opioid effects. This high potency, combined with their unpredictability on the recreational drug market, legal status in some regions, and economic appeal to drug producers, has contributed to a growing number of intoxications and fatalities involving nitazene analogues worldwide. This literature review focuses on the pharmaco-toxicology of nitazene opioids and the characteristics of their emergence on the NSO and broader recreational drug markets from 2019 onwards. Aspects that are covered include (a) a systematic approach to the naming of nitazene analogues, (b) trends, prevalence and identifications on the recreational drug market, (c) structure-activity relationships derived from recent <em>in vitro, in vivo,</em> and <em>in silico</em> research, (d) strategies for detection in biological samples and drug material, and (e) the current legal framework. Finally, innovative approaches to navigate this complex landscape are discussed, together with an outlook for the future.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"275 ","pages":"Article 110470"},"PeriodicalIF":4.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACVR1 drives neuropathic pain by regulating NLRP3-Induced neuronal pyroptosis through the p38 and Smad1/5/8 pathways","authors":"Xiaoxu Zhang ,&nbsp;Yuxin Miao ,&nbsp;Zongxiao Li ,&nbsp;Haoyue Xu ,&nbsp;Zejun Niu","doi":"10.1016/j.neuropharm.2025.110469","DOIUrl":"10.1016/j.neuropharm.2025.110469","url":null,"abstract":"<div><h3>Background</h3><div>Neuropathic pain is characterized by sustained pain hypersensitivity caused by nerve injury. The molecular mechanisms underlying this condition remain poorly understood. This study aims to elucidate the role of ACVR1 and its downstream pathways in mediating neuropathic pain through neuronal pyroptosis and neuroinflammation.</div></div><div><h3>Methods</h3><div>A spared nerve injury (SNI) model was established both in male and female mouse to induce neuropathic pain. Behavioral tests, Western blot, PCR, and immunofluorescence were used to assess the expression of ACVR1, p-Smad1/5/8, p-p38, and pyroptosis-related proteins (NLRP3, Caspase-1, and GSDMD-N). ACVR1, p38, and Smad1/5/8 were pharmacologically inhibited to evaluate their roles in neuropathic pain and pyroptosis.</div></div><div><h3>Results</h3><div>Behavioral analysis confirmed successful SNI model establishment, marked by reduced paw withdrawal thresholds (PWT). Protein and mRNA expression analysis revealed significant upregulation of ACVR1, p-Smad1/5/8, and p-p38 in the spinal cord, particularly in neurons. Furthermore, SNI enhanced pyroptosis-related protein expression, including NLRP3, Caspase-1, GSDMD-N, IL-1β and IL-18. Inhibition of ACVR1 alleviated mechanical allodynia, reduced neuronal pyroptosis, and decreased serum IL-1β and IL-18 levels. Similarly, p38 inhibition mitigated NLRP3-induced pyroptosis without altering ACVR1 expression. In contrast, Smad1/5/8 inhibition by DMH-1 effectively reduced pyroptosis and inflammation via NLRP3 but had no effect on p38 phosphorylation. Combined p38 and Smad1/5/8 pathway inhibition synergistically decreased pyroptosis-related protein expression, highlighting their interactive roles in ACVR1-mediated neuropathic pain.</div></div><div><h3>Conclusion</h3><div>These findings suggest that ACVR1 exacerbates neuropathic pain by activating neuronal pyroptosis and neuroinflammation via the p38 and Smad1/5/8 pathways. Targeting ACVR1 and its downstream signaling pathways may offer novel therapeutic strategies for neuropathic pain.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110469"},"PeriodicalIF":4.6,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The major component of Heteractis magnifica sea anemone venom, RpIII, exhibits strong subtype selectivity for insects over mammalian voltage-gated sodium channels","authors":"Oksana Sintsova ,&nbsp;Steve Peigneur ,&nbsp;Rimma Kalina ,&nbsp;Nadezhda Otstavnykh ,&nbsp;Mikhail Garbuz ,&nbsp;Anna Klimovich ,&nbsp;Nadezhda Priymenko ,&nbsp;Margarita Shamatova ,&nbsp;Aleksandra Pavlenko ,&nbsp;Sergey Kozlov ,&nbsp;Irina Gladkikh ,&nbsp;Marina Isaeva ,&nbsp;Jan Tytgat ,&nbsp;Elena Leychenko","doi":"10.1016/j.neuropharm.2025.110466","DOIUrl":"10.1016/j.neuropharm.2025.110466","url":null,"abstract":"<div><div>Voltage-gated sodium channels (Na_V) are molecular targets for the development of drugs for the treatment of diseases such as epilepsy, neuropathic pain, long QT syndrome, etc., as well as for insecticides. Therefore, the search for novel selective Na_V channel ligands is relevant. Using amplicon deep sequencing of tentacle cDNA libraries from sea anemones <em>Heteractis magnifica</em>, 36 transcripts related to RpIII neurotoxin, a Na_V channel modulators, were revealed. The recombinant RpIII was moderately toxic for mice (LD₅₀ 0.030 ± 0.004 mg/kg) but did not demonstrate any activity towards Na_V in human SH-SY5Y cells. The toxin inhibited inactivation of heterologously expressed mammalian, insect, and arachnid Na_V channels with higher specificity to insect channels. Cockroach (<em>Blattella germanica</em>) sodium channel BgNa_V1 (EC₅₀ of 2.4 ± 0.2 nM) and yellow fever mosquito (<em>Aedes aegypti</em>) channel AaNa_V1 (EC₅₀ of 1.5 ± 0.3 nM) were the most sensitive to RpIII, while mammals Na_V had EC₅₀ values above 100 nM except mNa_V1.6 (EC₅₀ of 43.8 ± 3.6 nM). The low nanomolar RpIII affinity to insect AaNa_V1 may be explained by the extensive intermolecular contacts found by docking study. According to the predicted data, the toxin lands on the ion channel between voltage-sensing domain IV and pore domain I, also known as toxin site 3, followed by stabilizing the channels in the open state what was measured at electrophysiological experiments.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110466"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin attenuates trimethyltin chloride-induced hippocampal neurotoxicity through SIRT3/NRF2/HO-1 activation","authors":"Ning Ding ,&nbsp;Pengyu Wang ,&nbsp;Yu Fang ,&nbsp;Yuanyuan Hu ,&nbsp;Wei Wang ,&nbsp;Jiping Wei ,&nbsp;Jun Yu ,&nbsp;Fei Cai","doi":"10.1016/j.neuropharm.2025.110461","DOIUrl":"10.1016/j.neuropharm.2025.110461","url":null,"abstract":"<div><div>Trimethyltin chloride (TMT), a potent neurotoxicant, induces hippocampal damage associated with neuroinflammation and synaptic dysfunction, mimicking key features of neurodegenerative disorders. Luteolin (LUT), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate. This study investigated the neuroprotective effects of LUT against TMT-induced hippocampal damage and explored the underlying mechanisms involving the SIRT3/NRF2/HO-1 signaling pathway.</div><div>In a murine model, LUT treatment (20 mg/kg, 14 days) significantly alleviated TMT-induced behavioral deficits, seizures, and ultrastructural hippocampal damage. Mechanistically, LUT restored synaptic protein expression (PSD95, SYN1, SYP) and suppressed neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-18) and glial activation (GFAP, IBA1). In vitro studies using SIRT3 inhibition confirmed the pathway's centrality to LUT's effects.</div><div>These results position LUT as a multi-target therapeutic candidate for hippocampal-related disorders, with dual efficacy in synaptic repair and anti-inflammatory modulation. Critically, this work bridges preclinical findings to clinical translation, suggesting LUT's applicability in neurotoxicant exposure scenarios or early neurodegenerative disease interventions. Further validation of bioavailability and safety profiles could accelerate its transition to clinical trials.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110461"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral economics of polysubstance use: The role of orexin-1 receptors in nicotine-induced augmentation of synthetic opioid consumption","authors":"Sarah C. Honeycutt,&nbsp;Elizabeth A. Gilles-Thomas,&nbsp;David D. Lichte,&nbsp;Shannon L. McSain,&nbsp;Ashmita Mukherjee,&nbsp;Gregory C. Loney","doi":"10.1016/j.neuropharm.2025.110467","DOIUrl":"10.1016/j.neuropharm.2025.110467","url":null,"abstract":"<div><div>Nicotine and opioid use disorders are highly comorbid in clinical populations. Ongoing nicotine administration facilitates opioid consumption in both rodents and humans. Moreover, preclinical studies support that former exposure to nicotine solely during adolescence augments opioid consumption in adulthood similarly to acute nicotine administration. This suggests that developmental nicotine exposure persistently alters the neural substrates underlying motivation in a manner that resembles the acute pharmacological actions of nicotine. The orexin system mediates motivation to consume opioids in large part through signaling at orexin-1 receptors (ORX1Rs). Both developmental nicotine exposure and acute nicotine administration profoundly alter functioning of the orexin system which may mediate the reinforcing enhancing properties of nicotine. Here, we used behavioral economic procedures to generate demand curves for consumption of the synthetic, short-acting, μ-opioid receptor agonist remifentanil (RMF) in adulthood following prior adolescent nicotine exposure (ANE) and again following reintroduction of acute nicotine administration (ANA). We found that ANE was sufficient to augment multiple indices of the motivational value of RMF in adulthood and these effects were further exacerbated by ANA given during RMF self-administration sessions. Additionally, we demonstrate that systemic antagonism of ORX1Rs with SB-334867 is more efficacious in limiting motivation for RMF in nicotine-exposed rats relative to controls and this differential efficacy was even greater in ANA conditions relative to former ANE. These findings support that nicotine-induced facilitation of orexin signaling may mechanistically contribute to augmented opioid consumption offering critical insight for treatment options for a population that is particularly vulnerable to developing opioid use disorder.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110467"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease","authors":"Tong Zhang ,&nbsp;Yuequ Zhang ,&nbsp;Pascal Chameau ,&nbsp;Tingting Chen ,&nbsp;Alejandro Marmolejo-Garza ,&nbsp;Wanda Douwenga ,&nbsp;Amalia M. Dolga ,&nbsp;Helmut W. Kessels ,&nbsp;Martina Schmidt ,&nbsp;Ulrich L.M. Eisel","doi":"10.1016/j.neuropharm.2025.110468","DOIUrl":"10.1016/j.neuropharm.2025.110468","url":null,"abstract":"<div><div>Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neuronal cultures. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 min before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110468"},"PeriodicalIF":4.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aged mice exhibit faster acquisition of intravenous opioid self-administration with variable effects on intake","authors":"Amanda L. Sharpe ,&nbsp;Laci R. Liter ,&nbsp;Darius Donohue ,&nbsp;Kelsey A. Carter ,&nbsp;Patricia Vangeneugden ,&nbsp;Sofia M. Weaver ,&nbsp;Michael B. Stout ,&nbsp;Michael J. Beckstead","doi":"10.1016/j.neuropharm.2025.110464","DOIUrl":"10.1016/j.neuropharm.2025.110464","url":null,"abstract":"<div><div>Although opioid abuse is more prevalent in young individuals, the rates of opioid use, overdose, and use disorders continue to climb among the elderly. Little is known about the biology underlying abuse potential in a healthy, aged population, in part due to technical and logistical difficulties testing intravenous self-administration in aged rodents. The goal of this study was to address a critical gap in the literature regarding age-dependent effects in opioid (remifentanil and fentanyl) self-administration. Male and female C57Bl/6J and C57Bl/6NJ mice were divided into young (mean: 19 weeks) and old (mean: 101 weeks) groups and were trained to self-administer intravenous fentanyl or remifentanil in daily operant sessions. Acquisition, intake, and cue-responding after forced abstinence were measured for both drugs, and a dose-response curve and dose-escalation were conducted for remifentanil and fentanyl, respectively. Surprisingly, old mice learned to self-administer both remifentanil and fentanyl faster and more accurately than young mice. Baseline intake of remifentanil was also greater in old mice compared to the young group; however, we did not see increased intake of fentanyl with age at either dose tested. Furthermore, old mice showed greater responding for cues previously associated with remifentanil after a forced abstinence, but this result was not observed with fentanyl. This first report of opioid self-administration in greater than 20-month-old mice suggests that old mice have an increased vulnerability for opioid use compared to younger counterparts, underscoring the importance of future work to uncover the biological mechanisms that are responsible.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"274 ","pages":"Article 110464"},"PeriodicalIF":4.6,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}