Neuropharmacology[JOURNAL]
Sun
200 papers
Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats.
Antila H, Jalonen SC, Persson NDÅ … +3 more , Peltoniemi M, Lohela TJ, Lilius TO
Neuropharmacology · 2026 Apr · PMID 41485517 · Publisher ↗
BACKGROUND: The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α-adrenergic receptor agonist, enhances perivascular cerebrosp...
BACKGROUND: The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α-adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α-adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α-adrenergic antagonist vatinoxan, we evaluated the role of physiological parameters on the glymphatic-enhancing properties of dexmedetomidine. METHODS: The effects of vatinoxan on the EEG spectral signature of dexmedetomidine and physiological parameters were investigated in female Sprague-Dawley rats. The whole-body distribution of intracisternally infused radiolabeled CSF tracer technetium-99m-labeled diethylenetriaminepentaacetic acid ([ᵐTc]Tc-DTPA) was quantified utilizing single-photon emission computed tomography (SPECT). RESULTS: While vatinoxan had no influence on the EEG spectral signature of dexmedetomidine sedation, it alleviated the peripheral effects, such as peripheral vasoconstriction, hyperglycemia, diuresis, and hyperosmolality. Vatinoxan created a unique CSF tracer distribution pattern by elevating the cortical tracer availability, quantified as area under the time-activity curve (AUC), by 36 % (AUC ratio, 1.36; 95 % CI, 1.0-1.8), increasing the maximum tracer concentration (C) in the intracranial space by 39 % (C ratio, 1.39; 95 % CI, 1.06-1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC ratio, 0.75; 95 % CI, 0.66-0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC ratio, 4.6; 95 % CI, 2.7-7.8). CONCLUSIONS: Antagonism of peripheral α-adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.
Spinal Shati/nat8l regulates mechanical hyperalgesia through NAAG-mGluR3 signaling in neuropathic pain.
Miyamoto K, Tatsuta K, Sumi K … +7 more , Uno K, Tokoro K, Muramatsu SI, Izuo N, Kume K, Nitta A, Ohsawa M
Neuropharmacology · 2026 Apr · PMID 41482212 · Publisher ↗
Shati/nat8l catalyzes the synthesis of N-acetylaspartate (NAA), a precursor for N-acetylaspartylglutamate (NAAG), an endogenous agonist of group II metabotropic glutamate receptor 3 (mGluR3). Although spinal mGluR3 is kn...
Shati/nat8l catalyzes the synthesis of N-acetylaspartate (NAA), a precursor for N-acetylaspartylglutamate (NAAG), an endogenous agonist of group II metabotropic glutamate receptor 3 (mGluR3). Although spinal mGluR3 is known to modulate nociceptive signaling, the functional role of Shati/nat8l in pain transmission has remained unclear. In this study, we investigated the involvement of spinal Shati/nat8l in mechanical nociceptive processing and neuropathic pain. We found that Shati/nat8l knockout (Shati-/-) mice exhibited a significantly decreased mechanical pain threshold compared to wild-type controls. This hypersensitivity was reversed by adeno-associated virus (AAV)-mediated expression of Shati/nat8l in the spinal dorsal horn. Intrathecal administration of NAAG-but not NAA-restored mechanical thresholds in Shati-/- mice, and this effect was blocked by the group II mGluR antagonist LY341495. In addition, treatment with LY341495 showed antinociceptive effect in normal mice at higher doses. In a peripheral nerve injury model, expression of Shati/nat8l mRNA in the ipsilateral dorsal horn was significantly decreased. Importantly, AAV-mediated restoration of Shati/nat8l expression in the dorsal horn alleviated neuropathic mechanical hyperalgesia and normalized Shati/nat8l mRNA levels. These findings suggest that downregulation of spinal Shati/nat8l contributes to mechanical hypersensitivity by impairing the NAAG-mGluR3 signaling pathway. Targeting the Shati/nat8l-NAAG-mGluR3 axis may offer a novel therapeutic strategy for the treatment of neuropathic pain.
TRPC6 mediates neuronal hyperexcitability in the lateral habenula to drive trigeminal neuralgia-associated anxiety.
Hu F, Liu Z, Min X … +10 more , Zhang K, Zhao H, Liu W, Tao Y, Jia Q, Gao Y, Meng X, Wang Y, Wu H, Cui W
Neuropharmacology · 2026 Apr · PMID 41478600 · Publisher ↗
Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). Howev...
Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). However, the mechanisms underlying this hyperexcitability remain unclear. Here, we show that partial transection of the infraorbital nerve (pT-ION) significantly upregulated the expression of transient receptor potential canonical 6 (TRPC6), β isoform of calcium/calmodulin-dependent protein kinase II (βCaMKII), phosphorylated extracellular regulated kinase (p-ERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in the LHb. Pharmacological blockade of either TRPC6 or βCaMKII effectively reversed pT-ION-induced mechanical hypersensitivity and anxiety-like behaviors. TRPC6 overexpression in the LHb reproduced the behavioral and electrophysiological phenotypes observed in pT-ION mice, including increased LHb neuronal excitability. In contrast, bilateral knockdown of TRPC6 attenuated both pain- and anxiety-like behaviors and normalized neuronal activity in the LHb. Our study identified TRPC6 as a key mediator of LHb neuronal hyperexcitability, contributing to trigeminal neuralgia-associated pain and anxiety via the βCaMKII/ERK/CREB pathway, and suggests its potential as a target for treatment.
Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and A2a receptor-expressing medium spiny neurons in nucleus accumbens core and shell.
Mount KA, Kuhn HM, Hwang EK … +2 more , Beutler MM, Wolf ME
Neuropharmacology · 2026 Apr · PMID 41456815 · Full text
A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases o...
A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naïve animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions after forced abstinence from extended-access oxycodone or saline self-administration, using male and female wild-type and transgenic rats. Before incubation (abstinence days 1-2), CP-AMPAR upregulation was not detected in either D1 or A2a (D2) receptor-expressing MSN. After incubation had stably plateaued (abstinence days 17-33), CP-AMPARs were elevated in both MSN subtypes in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell prevents expression of oxycodone incubation. However, CP-AMPAR upregulation on both MSN subtypes contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.
Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach.
Fiore M, Saltarelli S, De Mastro L … +6 more , D'Ambrosio E, Ianniello A, Bertolino A, Pergola G, Favia M, Rampino A
Neuropharmacology · 2026 Mar · PMID 41453617 · Publisher ↗
BACKGROUND: Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In...
BACKGROUND: Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In vitro cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function. METHODS: We identified published scientific literature in the PubMed database using the following search strategy: ("antipsychotic" OR "olanzapine" OR "clozapine" OR "risperidone" OR "quetiapine" OR "haloperidol") AND ("metabolic syndrome" OR "insulin action" OR "insulin resistance" OR "up-regulation" OR "down-regulation" OR "dyslipidemia") AND (cell models). RESULTS: Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS. CONCLUSIONS: Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level. In the final section of the manuscript, we highlight the potential of individual-specific stem-cell-based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.
Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors.
Chen W, Yokose J, Izuo N … +8 more , Yano Y, Kaigawa T, Kai N, Kamiyoshihara C, Ohkawa N, Shigetsura Y, Muramatsu SI, Nitta A
Neuropharmacology · 2026 Mar · PMID 41448359 · Publisher ↗
Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinf...
Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinforcing reward pathways and modulating neuronal plasticity. Teneurin-4 (TENM4), a type II transmembrane protein, is essential for neural development and for establishing precise synaptic connectivity. However, the specific role of TENM4 in the nucleus accumbens (NAc) during METH-induced reward remains unclear. Here, we found that repeated METH exposure selectively increased TENM4 protein expression in the nucleus accumbens (NAc), prompting us to investigate its function using an AAV-CRISPR-mediated knockdown (TENM4KD) targeted to the NAc in mice. TENM4KD significantly attenuated the development of METH-induced conditioned place preference, without altering METH-induced hyperlocomotion. This behavioral deficit was paralleled by blunted dopamine dynamics; fiber photometry revealed impaired predictive DA signals during conditioning, and microdialysis confirmed a reduction in both basal and METH-evoked DA levels. Mechanistically, this impairment was not due to damage to dopaminergic neurons themselves but was linked to a loss of local GABAergic neurons within the medial NAc and a compensatory upregulation of the dopamine transporter (DAT). These findings uncover a critical role for TENM4 in maintaining the integrity of local NAc circuits that govern reward learning. Thus, TENM4 emerges as a potential molecular target for therapeutic intervention, as manipulating its expression in the NAc disrupts local inhibitory signaling and reduces METH-induced addictive behaviors.
Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility.
Toft M, Meynier M, Lubrano Di Scampamorte H … +8 more , Vallée C, Salinas M, Zhang P, Tacco J, Gay AS, Bourinet E, Lingueglia E, Deval E
Neuropharmacology · 2026 Apr · PMID 41448358 · Publisher ↗
Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the...
Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FRCC‾RFamide) and a CFamide peptide (FRCRC‾Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FRCC‾RFamide peptide was much slower than those of FRCRC‾Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FRCC‾RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs' modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.
Dorsal raphe serotonergic neurons facilitate arousal from sevoflurane anesthesia by heterogeneously modulating neuronal activity in the basolateral amygdala.
Yang C, He Y, Cai M … +6 more , Wang S, Wang Y, Wang M, Wang H, Sun Y, Li J
Neuropharmacology · 2026 Mar · PMID 41448357 · Publisher ↗
BACKGROUND: Although the dorsal raphe nucleus (DRN) serotonergic neurons-which play a key role in consciousness-send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying the...
BACKGROUND: Although the dorsal raphe nucleus (DRN) serotonergic neurons-which play a key role in consciousness-send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive. METHODS: Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process. RESULTS: DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states. CONCLUSIONS: Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.
Targeting treatment-resistant social anxiety with sitagliptin: Effects on social fear and comorbid depressive-like behavior in a preclinical model.
Zoicas I, Kornhuber J
Neuropharmacology · 2026 Mar · PMID 41448356 · Publisher ↗
Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We prev...
Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor commonly used in the treatment of type 2 diabetes mellitus, effectively reduces social fear in mice subjected to social fear conditioning (SFC), an ethologically valid model of SAD. In the present study, we extend these findings by evaluating the efficacy of sitagliptin in reducing social fear and preventing the development of comorbid depressive-like behavior in acid sphingomyelinase-deficient (ASM-/-) mice, a genetically defined model of antidepressant-resistant emotional behavior. Chronic oral administration of sitagliptin (100 mg/kg/day) significantly reduced social fear in both male and female ASM+/+ and ASM-/- mice following SFC. Notably, sitagliptin also prevented the emergence of depressive-like behavior in both genotypes, as well as the increase in anxiety-like behavior observed specifically in ASM-/- mice, two hallmark comorbidities in the SFC model. These findings indicate that sitagliptin exerts dual-action effects on both primary and comorbid behavioral symptoms of SAD, including in individuals resistant to conventional antidepressant treatment. Given its established clinical use and safety profile, sitagliptin may represent a promising candidate for repurposing as an early intervention in complex, treatment-resistant forms of SAD.
Activation of 5-HT4 receptors reverses stress-induced dopamine system dysregulation.
Yang OJ, Perez SM, Lodge DJ
Neuropharmacology · 2026 Mar · PMID 41421509 · Full text
Stress can profoundly impact brain function, particularly in circuits regulating dopamine transmission. Increased mesolimbic dopamine activity is a well-documented consequence of stress exposure, contributing to maladapt...
Stress can profoundly impact brain function, particularly in circuits regulating dopamine transmission. Increased mesolimbic dopamine activity is a well-documented consequence of stress exposure, contributing to maladaptive behavioral and cognitive outcomes. Previous studies have identified a multisynaptic circuit that modulates dopamine neuron population activity in the ventral tegmental area (VTA), highlighting potential intervention points for mitigating stress-induced dopamine dysregulation. One such target is the 5-hydroxytryptamine-4 receptor (5-HT4R), which is expressed in key brain regions involved in dopamine system regulation, making it a promising candidate for pharmacological intervention. Here, we demonstrate that the 5-HT4R agonist BIMU8 effectively restores normal dopamine system function following stress exposure without altering baseline dopamine population activity in control male rats. Interestingly, in female rats, BIMU8 increased dopamine neuron population activity specifically during proestrus and estrus, suggesting that estrogen may play a role in serotoninergic modulation of mesolimbic dopamine function. Intracranial administration of BIMU8 into multiple brain regions indicates that its effects may be mediated through modulation of activity in the nucleus accumbens (NAc). These findings highlight 5-HT4R activation as a potential strategy for normalizing stress-induced alterations in dopamine system function.
HCN channel inhibitor ZD7288 in the lateral septum attenuates methamphetamine-induced behavior sensitization and relapse.
Lai S, Zhang W, Wang C … +8 more , Xu Y, Jiang S, Deng X, Zhu M, Chen G, Zhou K, Zhu Y, Wang K
Neuropharmacology · 2026 Mar · PMID 41419101 · Publisher ↗
Drug addiction involves dysregulation in limbic circuits, with the lateral septum (LS) playing a critical role in regulating drug reward and behavioral sensitization. Although chronic methamphetamine (METH) upregulates h...
Drug addiction involves dysregulation in limbic circuits, with the lateral septum (LS) playing a critical role in regulating drug reward and behavioral sensitization. Although chronic methamphetamine (METH) upregulates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the LS, the therapeutic potential of targeting these channels remains unclear. Here, using pharmacological approaches in mice, we demonstrate that the HCN channel inhibitor ZD7288-administered either locally into the LS or systemically-attenuates METH-induced memory retrieval, the development and expression of locomotor sensitization, without impairing memory acquisition. Furthermore, ZD7288 reduced both METH self-administration acquisition and cue-induced reinstatement. These effects were associated with the normalization of METH-induced neuronal hyperexcitability in the LS. Importantly, ZD7288 did not affect natural reward processing, such as food consumption and social interaction. Our results identify LS HCN channels as potential therapeutic targets for METH use disorder.
Enteric gliosis induced by TRPV4 alleviates intestinal excessive-motility through Ca signaling.
Tan Q, Li T, Xie H … +7 more , Chen Y, Chen S, Xu C, Yang F, Dong H, Chen J, Xiao W
Neuropharmacology · 2026 Mar · PMID 41412513 · Publisher ↗
BACKGROUND: Gastrointestinal (GI) dysmotility is a fundamental clinical issue in multiple diseases such as IBS, and there is a critical requirement for drugs to precisely modulate excessive GI motility. Enteric glial cel...
BACKGROUND: Gastrointestinal (GI) dysmotility is a fundamental clinical issue in multiple diseases such as IBS, and there is a critical requirement for drugs to precisely modulate excessive GI motility. Enteric glial cells (EGCs) are one of the major components of enteric nervous system, which is the key regulator of GI motility. EGCs undergo gliosis in response to multiple stimulation. Among them, mechanical stimulation is the most common stimulation and its motility-promoting effect been proved. However, whether mechanical stimulation could exert an motility-inhibitory effect remained to be elaborated. METHODS: GI motility was assessed by transit time, excreted/retained feces and water content. qPCR, western blotting and immunofluorescence were employed to analyze TRPV4 expression in EGCs. Furthermore, Enteric Gliosis was analyzed by proliferation, activation and neuroinflammation of EGCs. Intracellular Ca concentration were analyzed by Ca imaging. High-throughput sequencing was used to explore the mechanism of TRPV4. RESULTS: Firstly, TRPV4 activation suppressed GI motility in vivo. Secondly, TRPV4 was expressed in EGCs and activation of TRPV4 inhibited GI motility by promoting Enteric Gliosis. Furthermore, TRPV4 activation promotes EGCs Ca signaling, and TRPV4 is required for the regulation of EGCs Ca signaling and gliosis by CaCl, CaSR, and ATP. Lastly, TRPV4 activation promotes Enteric Gliosis and corrects abnormal GI motility of pathological diarrhea in vivo. CONCLUSION: TRPV4 were identified as a novel accelerator of Enteric Gliosis and suppressor of GI motility. Activation of TRPV4 effectively restoring GI motility homeostasis and offering a potential drug target for gastrointestinal dysmotility.
Age-dependent transcriptomic effects of morphine in the frontal cortex of female mice.
Savage J, Rai A, Lee JD … +7 more , Banahan J, Dujic K, Nunez M, Caldarone B, Ghoshal S, Slack FJ, Mavrikaki M
Neuropharmacology · 2026 Mar · PMID 41412512 · Full text
Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioi...
Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioid exposure. This study aimed to assess potential interactions between aging and opioid exposure. Three-month-old (young adult) and 19-month-old (aged) C57BL/6JN mice were assigned to either a morphine (3 mg/kg, i.p.) or saline group. A conditioned placed preference (CPP) task was used to assess reward sensitivity, while rotarod and beam walk tests were used to assess sensorimotor coordination. To assess for potential age-dependent effects of morphine on gene expression, we performed RNA sequencing in the prefrontal cortex (PFC). We found that morphine induced CPP in both age groups. Our results indicate impaired motor coordination in aged mice; however, morphine did not significantly affect motor coordination in either age group, although a trend toward an increased number of slips was observed in morphine-treated aged mice. Transcriptomic analysis revealed more robust effects of morphine on gene expression in the aged brain compared to the young brain. Interestingly, we found limited overlap between morphine-regulated genes in young and old mice, suggesting that the molecular effects of morphine are age-dependent. Taken together, while we found no significant interactions between morphine (at the tested dose) and aging in the behavioral assays, morphine caused age-dependent gene expression changes. Our findings suggest that age should be considered when prescribing opioids and that age-specific therapeutics may help address opioid use disorder in the elderly.
Downregulation of SNORD20 promotes ferroptosis in corpus cavernosum smooth muscle cells from diabetic rats through inducing the mitochondrial dysfunction.
Qin Y, Huang W, Zhou Y … +3 more , Chen Y, Li J, Wu Z
Neuropharmacology · 2026 Mar · PMID 41407097 · Publisher ↗
Erectile dysfunction (ED) disturbs the life of elderly men, and ferroptosis may be associated with the progression of ED. Small nucleolar RNAs (snoRNAs, 60-300 nucleotides) are non-coding regulatory RNAs mainly located i...
Erectile dysfunction (ED) disturbs the life of elderly men, and ferroptosis may be associated with the progression of ED. Small nucleolar RNAs (snoRNAs, 60-300 nucleotides) are non-coding regulatory RNAs mainly located in cell nucleolus, and SNORD20 was found to participate in the function of smooth muscle cells. However, the function of SNORD20 in ED remains unexplored. In the current research, protein and mRNA levels were examined using Western blot and RT-qPCR, respectively. Flow cytometry was employed to investigate apoptosis in cells. Mitochondrial function was examined using JC-1 and MitoSOX staining. Moreover, Fe levels were examined using iron kits and an erectile function study in rats was conducted to further explore the function of SNORD20 in diabetic ED. It was revealed that SNORD20 level was reduced in cells obtained from diabetic ED rats. Notably, SNORD20 overexpression increased the proliferation in corpus cavernosum smooth muscle cells from diabetic rats, and SNORD20 small interfering RNA exerted the opposite effect. SNORD20 knockdown markedly promoted cell apoptosis and ferroptosis, and induced mitochondrial dysfunction. In addition, silencing of SNORD20 induces mitochondrial dysfunction and induced ferroptosis via downregulating Nrf2 and GPX4 expressions in corpus cavernosum smooth muscle cells. Moreover, SNORD20 overexpression alleviated the erectile function of diabetic rats in vivo. Collectively, SNORD20 knockdown may promote ferroptosis in corpus cavernosum smooth muscle cells obtained from diabetic ED rats through inducing mitochondrial dysfunction, highlighting that this snoRNA may acts as a key player in ED.
Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation.
Li HR, Shi JZ, Zhang MJ … +9 more , Yun LY, Zhou YF, He YY, Li X, Du GH, Pang XB, Wang MW, Xie XM, Kou JJ
Neuropharmacology · 2026 Mar · PMID 41401902 · Publisher ↗
Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This...
Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ--induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.
Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis.
Liu Y, Zhang J, Li W … +5 more , Qu Q, Shan Z, Liu C, Jiao K, Hou X
Neuropharmacology · 2026 Mar · PMID 41391505 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.
Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.
Gomez-Almeria M, Martinez-Gonzalez L, Matos AT … +11 more , Rodriguez-Cueto C, Vaz AR, Martín-Baquero R, Pérez de la Lastra C, Infantes R, Fernández-Ruiz J, Palomo V, Gil C, Brites D, Martinez A, de Lago E
Neuropharmacology · 2026 Mar · PMID 41389988 · Publisher ↗
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival...
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3-18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.
Evaluating tocilizumab in ischemic stroke: Findings from the SPAN multicenter trial.
Chauhan A, Lee EA, Patel RB … +25 more , Kumskova M, Leira EC, Chauhan AK, Shi Y, Cao S, Koehler RC, Dhandapani KM, Khan MB, Kamat PK, Arbab A, Hess DC, Herman AL, Boisserand L, Sansing LH, Morais A, Jin X, Aykan S, Imai T, Ayata C, Nagarkatti KA, Lamb J, Diniz MA, Lyden PD, McCullough LD, Aronowski J
Neuropharmacology · 2026 Mar · PMID 41354124 · Publisher ↗
UNLABELLED: Inflammation, particularly mediated through interleukin-6 (IL-6) signaling, plays a critical role in stroke pathophysiology. High levels of IL-6 are associated with poor outcomes in stroke patients. Therapeut...
UNLABELLED: Inflammation, particularly mediated through interleukin-6 (IL-6) signaling, plays a critical role in stroke pathophysiology. High levels of IL-6 are associated with poor outcomes in stroke patients. Therapeutic inhibition of IL-6 signaling may offer a novel strategy to mitigate post-stroke damage and improve recovery. This study evaluated the efficacy of tocilizumab (TCZ), a clinically approved monoclonal antibody that blocks IL-6 receptor signaling, using data from the Stroke Preclinical Assessment Network (SPAN), a multi-center, randomized, blinded, placebo-controlled trial in preclinical stroke models. METHODS: We analyzed behavioral and MRI morphometry data from 701 rodents (both males and females; 1:1), including healthy young mice, diet-induced obese mice, aging mice, and spontaneously hypertensive rats (SHR) treated with saline (N = 348) or TCZ (N = 353) at a dose of 100 mg/kg for mice, 10 mg/kg for rats after middle cerebral artery occlusion (MCAO). RESULTS: In the overall mouse cohort, TCZ did not significantly improve long-term sensorimotor recovery or reduce brain tissue loss measured by MRI. However, aging mice exhibited modest motor function improvements. In SHRs, TCZ treatment resulted in improved sensory-motor function, particularly in male rats, as demonstrated by enhanced corner test scores on days 7 and 28 post-MCAO. While TCZ in SHRs provided early (day 2) cerebroprotection with reduced lesion volume, it did not alter subsequent tissue loss, as measured by tissue atrophy at day 30. CONCLUSIONS: These results suggest that IL-6R blockade with TCZ was associated with functional improvement in aging mice (modest) and hypertensive rats (notably males), without durable effect of brain tissue loss. No benefit was observed in the overall mouse cohort. These findings support IL-6 signaling as a viable therapeutic target and warrant further investigation into IL-6 receptor inhibition as a potential treatment strategy for stroke recovery.
Protective effects of phosphodiesterase 5 inhibitor, mirodenafil, on traumatic brain injury-induced neuronal death.
Park MK, Yang HW, Woo SY … +5 more , Jung HH, Shin SJ, Choi BY, Choung JJ, Suh SW
Neuropharmacology · 2026 Mar · PMID 41352712 · Publisher ↗
Traumatic brain injury (TBI) is a serious neurological condition caused by external physical forces that lead to extensive brain damage. The underlying pathological processes involve complex interactions, including neuro...
Traumatic brain injury (TBI) is a serious neurological condition caused by external physical forces that lead to extensive brain damage. The underlying pathological processes involve complex interactions, including neuronal death driven by cerebrovascular dysfunction, inflammation, and oxidative stress. A key contributor to these processes is the enzyme phosphodiesterase 5 (PDE5), which reduces cyclic guanosine monophosphate (cGMP) levels, leading to impaired vasodilation, reduced cerebral blood flow, and disruption of protective cellular pathways. Nitric oxide (NO) and zinc play significant roles in the progression of TBI-related damage. NO is a signaling molecule that supports cerebral blood flow and redox balance by boosting antioxidant defenses such as glutathione (GSH) levels. Zinc, an essential element for neural function, can become toxic in excess, contributing to oxidative stress and neuronal damage. During TBI, reduced NO availability and disrupted zinc homeostasis exacerbate these harmful effects, with increased PDE5 activity further depleting cGMP and limiting the activation of protective factors like Nrf2 and HO-1. This study explores the therapeutic potential of mirodenafil, a PDE5 inhibitor, in mitigating TBI-induced damage. Administered subcutaneously at 2 mg/kg, mirodenafil was evaluated through histological and biochemical techniques, including markers for neuronal degeneration, zinc accumulation, and NO synthesis. Results showed that mirodenafil reduced neuronal loss, regulated zinc levels, and restored NO signaling. These findings suggest that mirodenafil supports neuronal survival by preserving cGMP levels, enhancing NO function, and mitigating oxidative stress related to zinc dysregulation. This study highlights mirodenafil as a potential therapeutic option for limiting TBI-induced neuronal injury and preserving brain function.
Chemogenetic activation of an A2 nucleus of the solitary tract to lateral parabrachial nucleus noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in male and female mice.
Drinkuth CR, Dornellas APS, Guarino S … +2 more , Navarro M, Thiele TE
Neuropharmacology · 2026 Mar · PMID 41349794 · Full text
While there is strong evidence that the reinforcing effects of ethanol motivate seeking and consumption, ethanol produces aversive effects that limit consumption. We have previously found that in doses that support condi...
While there is strong evidence that the reinforcing effects of ethanol motivate seeking and consumption, ethanol produces aversive effects that limit consumption. We have previously found that in doses that support conditioned taste aversion (CTA) learning ethanol induces activity of noradrenergic (NE+) neurons of the A2 subregion of the nucleus of the solitary tract (NTS) as well as neurons within the lateral parabrachial nucleus (L-PBN), regions that have been implicated in integrating aversive responses. Here we provide evidence of a NE + circuit arising from the A2 and innervating the L-PBN in tyrosine hydroxylase (TH)-ires-cre mice. Next, we used male and female TH-ires-cre mice in tandem with an intersectional chemogenetic approach to assess the role of the NE + A2 to L-BPN circuit in modulating binge-like ethanol intake as well as unconditioned aversive behavior. Using "drinking in the dark" (DID) procedures we found that activating this circuit significantly blunted binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose solution intake. Furthermore, silencing this pathway during light cycle drinking revealed a trend of increased ethanol intake and an associated significant increase of BECs with no changes in sucrose intake. Additionally, activation of this circuit, as well as peripheral administration of the emetic agent LiCl, significantly increased the emission of mid-frequency vocalizations (MFVs) in mice, a phenotype reflecting aversive reactivity. The present findings provide novel evidence of a NE + A2 to L-PBN circuit in the modulation of binge-like ethanol intake and aversive responses.
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