Neuropharmacology[JOURNAL]
Sun
200 papers
Identification of key determinants in α subunit for α-conotoxin [D1G, ΔQ14]LvIC selectively targeting rat α6/α3β4 nicotinic acetylcholine receptor.
An B, Tang Z, Hu K … +5 more , Wei P, Zhangsun D, Zhu X, Yu J, Luo S
Neuropharmacology · 2026 Jun · PMID 42276205 · Publisher ↗
nAChRs containing α6 subunit (α6* nAChRs) are identified as being involved in Parkinson's disease, dyskinesia, drug addiction, and other disorders. Among these, α6β4 nAChR is recognized as a highly promising target for t...
nAChRs containing α6 subunit (α6* nAChRs) are identified as being involved in Parkinson's disease, dyskinesia, drug addiction, and other disorders. Among these, α6β4 nAChR is recognized as a highly promising target for the development of non-opioid analgesics. However, the research advancement on α6β4 nAChR has been hindered primarily by the overlapping tissue distribution with highly homologous α3β4 nAChR, as well as the scarcity of subtype-specific ligands. Recently, the α-conotoxin analogue [D1G, ΔQ14]LvIC was identified to exhibit remarkable selectivity for rα6/α3β4 nAChR with an IC of 19 nM, while showing negligible inhibitory activity against other subtypes, including closely related rα3β4 (IC > 10 μM), demonstrating exceptional subtype selectivity and potency compared to previously reported ligands for this receptor. In this study, we employed a combined approach of PCR-mediated site-directed mutagenesis and two-electrode voltage clamp electrophysiology to identify the determinants governing the [D1G, ΔQ14]LvIC selectivity. 67 single-point mutants of rα6/α3β4 nAChR were generated, systematically replacing each differing residue in rα6/α3 to rα3 subunit. The activity of [D1G, ΔQ14]LvIC was subsequently assessed on the native receptor and its mutants. As the results showed, E152, I157, and T195 in rα6/α3 subunit were identified as essential for [D1G, ΔQ14]LvIC selectivity. Inverse and multiple-point mutants were subsequently constructed and assessed for further validation. Molecular modeling further shed light on the molecular basis for the unique interaction between [D1G, ΔQ14]LvIC and rα6/α3β4 nAChR. These findings advance our understanding of α6β4 nAChR-ligand interactions and pave the way for the rational design of targeted therapeutics.
Exploring the synergistic mechanism of combined hypnotic drugs on sleep in mice based on transcriptomics.
Bai R, Liu Y, Yin Y … +3 more , Wu F, Song Y, Gao Y
Neuropharmacology · 2026 Jun · PMID 42264298 · Publisher ↗
OBJECTIVES: To investigate the effects of the combined administration of dexmedetomidine and eszopiclone on sleep in mice, and to elucidate the underlying molecular mechanisms at the gene expression level. METHODS: Takin...
OBJECTIVES: To investigate the effects of the combined administration of dexmedetomidine and eszopiclone on sleep in mice, and to elucidate the underlying molecular mechanisms at the gene expression level. METHODS: Taking the loss of righting reflex in mice as sleep indicator, the drug interactions between dexmedetomidine and eszopiclone were systematically evaluated at nine ratios by the Chou-Talalay method. Transcriptome sequencing was applied to screen for key pathways and genes through differentially expressed genes analysis, GO functional annotation and KEGG enrichment analysis. Additionally, qRT-PCR was used to validate the screened key genes. RESULTS: dexmedetomidine and eszopiclone exhibited synergistic hypnotic effects at ED ratios of 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1, with the strongest synergism occurring at the equal ratio (5:5). The combination group showed significant enrichment in the neuroactive ligand-receptor interaction pathway. Within this pathway, expression of the genes Gh and Prl was significantly upregulated, whereas that of Glra1, Npsr1 and Trpv1 was significantly downregulated. These expression changes were confirmed by qRT-PCR. CONCLUSION: The study reveals that co-administration of dexmedetomidine and eszopiclone produces a significant synergistic hypnotic effect in mice, with the strongest synergy demonstrated when the drugs are combined at the equal ratio. The underlying mechanism mediating their synergistic modulation of sleep may be associated with the upregulation of Gh and Prl genes as well as the downregulation of Glra1, Npsr1 and Trpv1 genes in the neuroactive ligand-receptor interaction pathway.
Role of accumbens medium spiny neurons subtypes in reinstatement to ketamine cues in male and female Long Evans rats.
Hagarty DP, Dawoud A, Guerrero AB … +8 more , Etienne K, Jennings SD, Martinez K, Csernecky O, Schoepfer KJ, Strong CE, Saland SK, Kabbaj M
Neuropharmacology · 2026 Jun · PMID 42252079 · Publisher ↗
Ketamine, a non-competitive N-Methyl-D-Aspartate receptor antagonist, was approved for use with Treatment-Resistant Depression (TRD) and is currently in clinical trials for treating substance use disorder (SUD), and Post...
Ketamine, a non-competitive N-Methyl-D-Aspartate receptor antagonist, was approved for use with Treatment-Resistant Depression (TRD) and is currently in clinical trials for treating substance use disorder (SUD), and Post Traumatic Stress Disorder. However, ketamine is an addictive drug, and thus we need to better understand ketamine's mechanism of action in addiction to reliably assess the safety of repeated use as a treatment for several psychopathologies. The nucleus accumbens (NAc), the brain's major reward hub, plays an important role in the salience of drug-related cues. The NAc is comprised of 90-95% GABAergic medium spiny neurons (MSNs) and consists of the Core and Shell. MSNs consist of two distinct subpopulations: Dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) expressing MSNs that roughly positively and negatively regulate behavior, respectively. However, the cell-type specific role of D1R/D2R-containing MSNs in the NAc and the underlying circuitry mediating ketamine reinstatement remains unknown. To this end, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADD, hM4Di) in Drd1a-iCre and Drd2-iCre transgenic rats to assess the roles of the two distinct NAc MSNs during ketamine cue-induced reinstatement. Our results showed an important role of D1R, but not D2R, NAc MSNs in reinstatement to ketamine cues. Future work will focus on identifying the underlying circuit driving cue-induced reinstatement and roles of the direct and indirect pathways.
Chronic alcohol exposure produces pathology-dependent corticostriatal circuit remodeling in Aβ- and tau-based mouse models of Alzheimer's disease.
Huang Y, Xie X, Huang Z … +5 more , Gangal H, Chen R, Wang X, Li J, Wang J
Neuropharmacology · 2026 Jun · PMID 42252078 · Publisher ↗
Chronic alcohol consumption is a major risk factor for Alzheimer's disease (AD), yet how alcohol exposure alters neural circuits under distinct pathological conditions remains poorly understood. Here, we used a humanized...
Chronic alcohol consumption is a major risk factor for Alzheimer's disease (AD), yet how alcohol exposure alters neural circuits under distinct pathological conditions remains poorly understood. Here, we used a humanized Aβ knock-in model (hAPP-KI) and a tauopathy model (PS19) to test how the same alcohol exposure affects distinct pathological contexts. In hAPP-KI mice, alcohol exposure increased cortical Aβ burden, enhanced excitatory synaptic transmission in the medial prefrontal cortex (mPFC), and reduced glutamatergic transmission from the mPFC to the dorsomedial striatum (DMS). In contrast, in PS19 mice, alcohol exposure increased tau phosphorylation and elevated mPFC-to-DMS glutamatergic transmission without altering local cortical excitatory input. Alcohol exposure was also associated with distinct microglial responses across pathological contexts. To assess microglial contributions to cortical excitatory regulation, we depleted microglia in wild-type mice and observed enhanced cortical glutamatergic transmission. Together, these findings suggest pathology-dependent circuit remodeling and microglial responses associated with alcohol exposure in AD models.
Prefrontal cortex projections to the mediodorsal thalamus are uniquely vulnerable to the effects of early adolescent alcohol consumption.
Mejia-Gomez H, Fawcett-Patel J, Maxwell FM … +3 more , Collins G, Zakris SA, Salling MC
Neuropharmacology · 2026 Jun · PMID 42252077 · Publisher ↗
A bevy of clinical and preclinical evidence has established that the prefrontal cortex (PFC) is negatively affected by heavy alcohol consumption during adolescence, yet the specific neuroadaptations to the PFC associated...
A bevy of clinical and preclinical evidence has established that the prefrontal cortex (PFC) is negatively affected by heavy alcohol consumption during adolescence, yet the specific neuroadaptations to the PFC associated with adolescent alcohol are not well understood. Using a retrograde viral approach and ex vivo whole-cell patch-clamp electrophysiology, we examined the impact of adolescent alcohol consumption on neuronal excitability in specific projections from the prelimbic PFC to the contralateral PFC (PFC), nucleus accumbens (PFC), or mediodorsal thalamus (PFC). Following adolescent alcohol consumptions, we observed several electrophysiological effects specifically to PFC pyramidal neurons (PNs) including increased intrinsic excitability due to a reduction in the hyperpolarization-activated, nonselective cation current (I) and decreased excitatory synaptic neurotransmission. Many of these effects were persistent in male mice as they were observed after 10 days of abstinence in PFC PNs and were not seen when IA EtOH was initiated in adulthood or even in late adolescence. To further characterize the consequences of adolescent alcohol consumption on PFC dependent behaviors, we performed touchscreen-based operant tasks aimed at more directly assessing PFC-dependent cognition. We found that cognitive flexibility and working memory performance were not largely affected by adolescent alcohol, however, additional analyses revealed blunted task shifting and delayed response latencies. The PFC circuit has previously been implicated in response timing and attentional processes and therefore exposure to alcohol during the early adolescent window may disrupt executive function through adaptations to PFC circuitry.
Acute restraint stress exacerbates compulsive grooming in male Sapap3 knockout mice: Critical role of nucleus accumbens D2 receptors.
Dai D, Wang S, Wang Y … +7 more , Yu J, Chen Y, Shi H, Lu S, Wang Y, Ma R, Fang J
Neuropharmacology · 2026 Jun · PMID 42250868 · Publisher ↗
Intrusive thoughts and repetitive behaviors are hallmark features of obsessive-compulsive disorder (OCD). Acute stress is closely associated with the onset and severity of obsessive-compulsive symptoms, but the underlyin...
Intrusive thoughts and repetitive behaviors are hallmark features of obsessive-compulsive disorder (OCD). Acute stress is closely associated with the onset and severity of obsessive-compulsive symptoms, but the underlying mechanisms remain largely unclear. Recent studies have implicated the nucleus accumbens (NAc) in the interaction between stress and compulsive behaviors. In this study, we used Sapap3 knockout (KO) mice, a validated model of compulsive grooming, to examine how acute restraint stress (ARS) influences compulsive behaviors and their neural correlates. Compared with wild-type controls, KO mice displayed a significant stress-dependent increase in grooming behavior following ARS. This behavioral enhancement was accompanied by elevated population activity of NAc neurons, as revealed by in vivo calcium imaging. Furthermore, Sapap3 KO mice exhibited markedly reduced D2 receptor protein expression in the nucleus accumbens. Both optogenetic inhibition of D2 receptor-expressing medium spiny neurons (D2-MSNs) and pharmacological activation of D2 receptors with bromocriptine significantly attenuated acute restraint stress-induced compulsive grooming. These findings suggest that acute stress exacerbates compulsive behavior in Sapap3 KO mice, likely via further impairing D2 receptor function in the NAc, highlighting the critical role of NAc D2 receptors and D2-MSN activity in stress-triggered obsessive-compulsive symptoms.
Targeting P2X receptor signaling for chronic visceral pain and beyond.
Shen B, Zhang HH, Wang C … +7 more , Xu X, Zhang Y, Bai T, Chen H, Illes P, Tang Y, Xu GY
Neuropharmacology · 2026 Jun · PMID 42248408 · Publisher ↗
P2X receptors (P2XRs) are ATP-gated cation channels that play a pivotal role in chronic visceral pain (CVP). This review highlights the central contribution of the ATP-P2X3/4/7 axis in peripheral and central sensitizatio...
P2X receptors (P2XRs) are ATP-gated cation channels that play a pivotal role in chronic visceral pain (CVP). This review highlights the central contribution of the ATP-P2X3/4/7 axis in peripheral and central sensitization underlying CVP. Recent discoveries have identified the non-coding RNA miR-1306-3p as an endogenous nanomolar agonist of P2X3 receptors, coupling chronic stress to visceral pain via an epigenetic pathway. Moreover, persistent DNA methylation changes at the P2RX7 locus in spinal astrocytes create a "pain memory" that limits the durability of conventional antagonists. The first-generation P2X3/P2X7 antagonists (e.g., AF-219, AZD-9056, NC-2600) failed in clinical trials, primarily due to species-specific receptor pharmacology, the lack of ATP-based biomarkers for patient stratification, and irreversible central sensitization driven by epigenetic marks. To overcome these hurdles, we propose a precision-medicine framework that includes: (1) CRISPR-dCas9-based epigenome editing as a potential one-time "pain-memory eraser"; (2) patient stratification using sweat-ATP levels; and (3) human iPSC-derived neuron screening to improve translational predictability. This integrated approach holds promise not only for CVP related to irritable bowel syndrome (IBS), but also for other pain conditions.
Corrigendum to "Preventive effects of a standardized flavonoid extract of safflower in rotenone-induced Parkinson's disease rat model" [Neuropharmacology 217 (2022) 109209].
Ablat N, Liu R, Ablimit M … +5 more , Sun Y, Xu F, Zhao X, Han H, Pu X
Neuropharmacology · 2026 Jun · PMID 42243015 · Publisher ↗
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NOP receptor activation counteracts stress-induced migraine-like behaviors in mice.
Pola P, Sturaro C, Argentieri M … +5 more , Frezza A, Albanese V, Zaveri NT, Calò G, Ruzza C
Neuropharmacology · 2026 Jun · PMID 42242546 · Publisher ↗
Stress is a major trigger of migraine, yet the underlying mechanisms remain unclear. Previous evidence supports the nociceptin/orphanin FQ (N/OFQ)/NOP receptor system as a potential target for novel anti-migraine strateg...
Stress is a major trigger of migraine, yet the underlying mechanisms remain unclear. Previous evidence supports the nociceptin/orphanin FQ (N/OFQ)/NOP receptor system as a potential target for novel anti-migraine strategies, although its role in stress-induced and persistent migraine-like states remains unclear. We evaluated the role of the N/OFQ/NOP receptor system in a mouse model where repeated restraint stress induces periorbital mechanical allodynia (PMA) and primes responses to a subthreshold dose of nitroglycerin (GTN, 0.1 mg/kg). Experiments were performed in male mice, as a first study showed that stress did not sensitize females to subthreshold GTN under our conditions. Stress-induced PMA resolved in young mice but persisted for weeks in older animals, inducing a persistent migraine-like phenotype. GTN, inactive in naïve mice, evoked PMA only in previously stressed animals. NOP knockout did not alter animal susceptibility, whereas NOP stimulation with the brain-penetrant NOP agonist AT-403 (30 μg/kg) or the peripherally restricted agonist UFP-112 (10 pmol) prevented GTN-evoked PMA and reversed stress-induced PMA, including persistent allodynia in older adult mice. Comparable efficacy of UFP-112 and AT-403 supports the contribution of peripheral NOP receptors. Together, our findings expand the evidence beyond acute pharmacological models, supporting the potential of NOP agonists for the treatment of both acute and persistent migraine.
Endomorphin analogs CEMR-1 and CEMR-2 administered intravenously display potent antinociception with limited tolerance in acute, neuropathic and inflammatory pain.
Wang SY, Shi JJ, Liu WH … +6 more , Dai JR, Zhang YZ, Ning DY, Wang XF, Wu YJ, Wang CL
Neuropharmacology · 2026 Jun · PMID 42242545 · Publisher ↗
Endomorphins (EMs) hold substantial promise as therapeutic agents for pain management. Our earlier investigations established that the novel EMs analogs CEMR-1 and CEMR-2 acted as potent and selective μ-opioid receptor a...
Endomorphins (EMs) hold substantial promise as therapeutic agents for pain management. Our earlier investigations established that the novel EMs analogs CEMR-1 and CEMR-2 acted as potent and selective μ-opioid receptor agonists, displaying marked analgesic properties at the central level. This study aimed to evaluate the analgesic effects and tolerance profiles of CEMR-1 and CEMR-2 following intravenous (i.v.) administration across a range of preclinical pain models. Following tail vein injection, CEMR-1 and CEMR-2 produced potent and prolonged analgesia in acute pain, with minimal acute or chronic tolerance and no cross-tolerance to morphine. Among them, CEMR-1 particularly demonstrated potential as a non-tolerance-forming analgesic. Antagonist experiments further confirmed that the analgesic effects of these two analogs were primarily mediated by central opioid receptors. Furthermore, in neuropathic and inflammatory pain models, both analogs also exhibited notable analgesic efficacy after i.v. administration along with reduced tolerance-related side effects. Importantly, under neuropathic pain conditions, CEMR-1 and CEMR-2 almost did not induce chronic tolerance to their analgesic effects. The findings of this study demonstrated that the novel EMs analogs CEMR-1 and CEMR-2 exerted strong and sustained analgesic effects administered systemically and reduced tolerance. Therefore, CEMR-1 and CEMR-2 were promising candidate analgesics with minimal adverse effect of tolerance.
Corrigendum to "Erythropoietin targets parvalbumin-positive inhibitory neurons and microglia to promote plasticity in the thalamic reticular nucleus" [Neuropharmacology 297 (2026) 111025].
Gramuntell Y, Klimczak P, Curto Y … +6 more , Alcaide J, Garcia-Verellen E, Perez-Rando M, Nave KA, Ehrenreich H, Nacher J
Neuropharmacology · 2026 Jun · PMID 42236392 · Publisher ↗
Abstract loading — click title to view on PubMed.
Exploring the therapeutic potential of hesperidin nanoparticles, carbidopa-levodopa, or their combined administration in a rat model of reserpine-induced Parkinsonism.
Katreen Amin EH, Ibrahim IH, Khadrawy YA … +1 more , Mohammed HS
Neuropharmacology · 2026 Jun · PMID 42235750 · Publisher ↗
In the pursuit of novel and effective therapeutic strategies, this study investigates the effects of hesperidin nanoparticles (HSP NPs), either alone or in combination with Carbidopa-levodopa (CLD), in a reserpine-induce...
In the pursuit of novel and effective therapeutic strategies, this study investigates the effects of hesperidin nanoparticles (HSP NPs), either alone or in combination with Carbidopa-levodopa (CLD), in a reserpine-induced Parkinson's disease (PD) rat model. Rats were randomly assigned to five experimental groups: control, PD model, PD model + HSP NPs, PD model + CLD, and PD model + HSP NPs + CLD. Behavior was assessed by the open field and grip strength tests. Monoamine levels, oxidative stress, enzyme activity, tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) were analyzed in two brain areas; midbrain and striatum. Untreated rats exhibited motor deficits, a significant decrease in dopamine, norepinephrine, and serotonin levels, along with an increase in oxidative stress markers, monoamine oxidase, and acetylcholinesterase activities in both the midbrain and striatum compared to control values. Treatment with CLD or HSP NPs resulted in elevated levels of monoamines, restoring enzyme activity, and mitigating oxidative stress with partial improvement in motor activity. The combination of HSP NPs and CLD significantly restored Biochemical parameters in the midbrain and striatum, and decreased midbrain AChE activity. These findings underscore the potential of HSP NPs in mitigating neurochemical and behavioral alterations induced by reserpine in the rat PD model. According to the present promising preclinical data, HSP NPs could be investigated on other models of PD to ensure their antiparkinsonian effects. These preclinical results may represent a primary step toward using HSP NPs in human investigation.
Dorsal hippocampal CA3 to CA1 circuit maintains contextual cocaine memories in a rat model of drug relapse.
Qi S, Soto DA, Pruitt AY … +3 more , Ritchie JL, Reeves DA, Fuchs RA
Neuropharmacology · 2026 Jun · PMID 42235749 · Publisher ↗
Exposure to a cocaine-associated environment triggers drug craving and relapse by prompting the retrieval of drug-related long-term memories. Upon retrieval, memory traces enter a labile state during which they can be mo...
Exposure to a cocaine-associated environment triggers drug craving and relapse by prompting the retrieval of drug-related long-term memories. Upon retrieval, memory traces enter a labile state during which they can be modified until their reconsolidation into long-term memory stores. Disrupting labile memory traces is a promising therapeutic approach for treating neuropsychiatric disorders characterized by maladaptive memories, including substance use disorder. The dorsal hippocampus cornu ammonis 3 (dCA3) is a critical regulator of cocaine-memory strength, and the dorsal CA1 (dCA1) has been implicated in similar processes. Therefore, we tested the hypothesis that monosynaptic input from dCA3 to dCA1 is necessary for maintaining cocaine-memory strength, using circuit-specific optogenetic inhibition. Rats underwent cocaine self-administration training then extinction training in two distinct environmental contexts to acquire contextual cocaine and extinction memories, respectively. They were briefly re-exposed to the cocaine-predictive context then received intermittent dCA3-dCA1 circuit-specific photoinhibition or no photoinhibition immediately after the session (when memories were expected to be labile) or 6 h later (post reconsolidation). dCA3-dCA1 circuit photoinhibition immediately, but not 6 h, after memory retrieval, attenuated drug-seeking behavior in the cocaine-predictive context 72 h later. This effect was opsin-, light-, and context-dependent, and it positively correlated with a decrease in dCA1 neuronal activation at test. This effect was also more robust in female rats, consistent with sex-dependent compensatory synaptic plasticity. Together, these findings suggest that dCA3-dCA1 circuits encode labile cocaine memories, underlie their reconsolidation, or support subsequent long-term memory retrieval.
Unveiling the role of single versus repeated low-dose ketamine in attenuating doxorubicin-induced chemobrain and depression in rats: differential modulation of neuroinflammation, phosphorylated GLT-1, SERT, DAT, and BDNF/TrkB signaling.
Fahmy NG, Kamel NM, Khattab MM … +1 more , Muhammad RN
Neuropharmacology · 2026 Jun · PMID 42229837 · Publisher ↗
Doxorubicin (DOX), a widely utilized chemotherapeutic agent, is associated with significant adverse effects, including cognitive dysfunction (chemobrain) and depression. Ketamine (KET), the anesthetic, was off-label used...
Doxorubicin (DOX), a widely utilized chemotherapeutic agent, is associated with significant adverse effects, including cognitive dysfunction (chemobrain) and depression. Ketamine (KET), the anesthetic, was off-label used as antidepressant and got FDA approval in 2019 for treatment-resistant depression management. Hence, this study investigated the therapeutic efficacy of single [KET(S)] versus repeated [KET(R)] subanaesthetic ketamine in mitigating DOX-induced neurological alterations in rats. Forty-eight adult male Wistar rats were subdivided into four groups: control, DOX, KET(S) (DOX followed by a single KET dose, 15 mg/kg), and KET(R) (DOX followed by repeated KET doses, 15 mg/kg/day for 14 days). Results showed that DOX administration caused marked motor dysfunction, cognitive impairment and depression-like behavior, along with elevated neuroinflammation and disrupted neurotrophic signaling. Both KET regimens improved behavioral performance, suppressed systemic and local inflammation, evidenced by suppressing tumor necrosis factor-alpha and nicotinamide adenine dinucleotide phosphate oxidase activity. Also, KET(R) suppressed phosphorylation of key neurotransmitter transporters: phospho T53-dopamine transporter, phospho S563-glutamate transporter-1, and phospho T276-serotonin transporter, which led to enhanced hippocampal brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling. Notably, KET(R) produced superior behavioral and biochemical improvements compared to KET(S). Histopathological examinations corroborated these findings. Collectively, these data suggest that KET, particularly when administered repeatedly at low doses, could be a promising adjunctive therapy to enhance quality of life for cancer patients undergoing DOX chemotherapy. However, because key intermediate nodes were not directly measured and KET-only control groups were not included, the proposed mechanistic cascade should be regarded as a hypothetical integrative model that warrants further validation.
Spinal NLRP3 blockade reverses morphine-prolonged neuropathic pain and proinflammatory immune actions in prenatal alcohol-exposed male mice.
Pasmay AA, Pritha AN, Dadina S … +2 more , Carter JR, Noor S
Neuropharmacology · 2026 Jun · PMID 42229836 · Publisher ↗
Prenatal alcohol exposure (PAE) exerts long-term alterations in the adult neuroimmune system. Previous work showed that PAE exacerbates morphine-mediated immune responses, prolonging nerve injury-induced allodynia and pr...
Prenatal alcohol exposure (PAE) exerts long-term alterations in the adult neuroimmune system. Previous work showed that PAE exacerbates morphine-mediated immune responses, prolonging nerve injury-induced allodynia and promoting aberrant NLRP3-driven inflammation in both the periphery and spinal cord. Whether the spinal actions of NLRP3, arising from aberrant TLR4 activation, are critical in driving allodynia remains unknown. With a 25+ day-long time course study, using another previously established PAE model in mice, we reproduced these adverse effects of PAE and further examined whether spinal blockade of TLR4 or the NLRP3 reverses this pathological pain state by dampening proinflammatory actions in the spinal cord and dorsal root ganglia (DRG), critical relay nociceptive signaling regions. We demonstrate that pharmacological inhibition of either the spinal TLR4 receptor (Tak-242) or the NLRP3 inflammasome (MCC950) reverses established morphine-induced prolonged allodynia in nerve-injured male PAE mice. In the spinal cord, increased IL-1β, caspase-1, HMGB1, IL-18, and astrocyte activation were detected in PAE mice, which were dampened by MCC950 treatment. DRGs from allodynic PAE mice exhibited heightened expression of IL-1β, TNF-α, NLRP3, and caspase-1, as well as satellite glial and neuronal activation (Panx1 and TRPV1), which were reduced by MCC950. Despite allodynia reversal, inflammatory mediators persisted at the peripheral injury site in PAE mice. Together, these findings elucidate the spinal TLR4-NLRP3 axis as a modulator of morphine-prolonged allodynia and provide mechanistic insights into neuroimmune dysfunction underlying PAE-associated vulnerability and altered responses to opioid therapeutics.
Adenosine A1 receptor activation attenuates neuropathic pain by suppressing microglial ERK/NF-κB-mediated neuroinflammation.
Ding S, Bai J, Liu H … +5 more , Pei S, Feng X, Li P, Wang Y, Li Y
Neuropharmacology · 2026 Jun · PMID 42225243 · Publisher ↗
Neuropathic pain (NP) is tightly linked to neuroinflammation driven by aberrant activation of spinal microglia; however, the endogenous regulatory mechanisms that limit excessive microglial responses following nerve inju...
Neuropathic pain (NP) is tightly linked to neuroinflammation driven by aberrant activation of spinal microglia; however, the endogenous regulatory mechanisms that limit excessive microglial responses following nerve injury remain incompletely understood. Adenosine (ADO) is widely recognized as a homeostatic mediator released under conditions of tissue damage and stress, and activation of the adenosine A1 receptor (A1R) has been reported to exert antinociceptive effects at both spinal and peripheral levels. Nevertheless, the potential role of A1R as an endogenous modulator of microglial activation in NP, as well as the underlying signaling mechanisms, remains poorly defined. In this study, we found that A1R expression was markedly increased in spinal microglia after nerve injury. Notably, ATPγS-mediated damage-associated molecular pattern (DAMP) stimulation, but not lipopolysaccharide (LPS)-mediated inflammatory stimulation, increased microglial A1R expression. Pharmacological activation of A1R reversed the pro-inflammatory phenotypic shift of microglia and suppressed their excessive proliferation, resulting in significant attenuation of NP behaviors across different injury models. Mechanistically, A1R activation inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in microglia, thereby preventing activation and nuclear translocation of the nuclear factor-κB (NF-κB) p65 subunit, reducing the release of pro-inflammatory cytokines (PICs) and alleviating the neuroinflammatory microenvironment in the spinal dorsal horn. Taken together, our findings suggest that injury-associated upregulation of microglial A1R may act as a negative feedback mechanism that restrains microglial activation and neuroinflammation via the ERK/NF-κB signaling axis, providing mechanistic insight into endogenous neuroimmune regulation following nerve injury.
The antidepressant-like effect of adenosine A receptor over-expression in forebrain neurons does not involve an altered adenosine-mediated control of excitatory synaptic transmission.
Tomé AR, Real JE, Rial D … +9 more , Silva AC, Gonçalves FQ, Lemos C, Simões AP, Silva HB, Serchov T, Biber K, Agostinho P, Cunha RA
Neuropharmacology · 2026 Jun · PMID 42225242 · Publisher ↗
The action of different fast-acting antidepressant strategies, ranging from ketamine to deep brain stimulation, seems to involve an increased function of adenosine A receptors (AR). AR are mostly located in excitatory sy...
The action of different fast-acting antidepressant strategies, ranging from ketamine to deep brain stimulation, seems to involve an increased function of adenosine A receptors (AR). AR are mostly located in excitatory synapses and trigger a general inhibition of brain function. Thus, we now resorted to mice overexpressing AR in forebrain neurons (oeA1R) to test if and how synaptic AR were selectively engaged to control mood. We first confirmed that oeA1R mice displayed an anxiolytic and resilient behavior profile with no evident alteration of working or reference memory, but with increased learning flexibility. Surprisingly, there was no modification of the ability of AR agonists or antagonists (DPCPX) to control synaptic transmission or short-term plasticity in excitatory synapses of either prefrontal cortex or dorsal hippocampus of oeA1R compared to WT mice. Accordingly, the binding density of AR was mostly increased outside synapses (200% increase) rather than in synaptic membranes (20% increase) of the cerebral cortex. Moreover, the increased number of extra-synaptic AR were G-protein-coupled (i.e. potentially 'active') based on the displacement binding curves of the AR agonist CPA in cerebrocortical membranes. This prompts the correlative conclusion that the anxiolytic and antidepressive effects of increased AR levels might involve extra-synaptic AR rather increased AR function in synapses, which does not align with prevailing models emphasizing synaptic mechanisms in antidepressant action and paves the way to develop more selective antidepressants targeting these extra-synaptic AR.
GPR139-mediated cholinergic circuit from the medial septum to the ventral hippocampal CA3 modulates cognitive impairment in Alzheimer's disease.
Li H, Hou X, Qin C … +3 more , Li X, Wu X, Mu R
Neuropharmacology · 2026 Jun · PMID 42218995 · Publisher ↗
G-protein coupled receptor 139 (GPR139) has been detected in the medial septum (MS) cholinergic neuron, but its roles in cholinergic circuits associated with Alzheimer's disease (AD) remain unclear. Using a variety of ex...
G-protein coupled receptor 139 (GPR139) has been detected in the medial septum (MS) cholinergic neuron, but its roles in cholinergic circuits associated with Alzheimer's disease (AD) remain unclear. Using a variety of experimental approaches, including the establishment of AD mouse models, viral injection, immunohistochemistry, ELISA, TUNEL apoptosis assay, Golgi staining, electrophysiological recording, fiber photometry, and behavioral tests, we found that knockdown of GPR139 in MS cholinergic neurons exacerbated early-stage cognitive decline, apoptosis, and synaptotoxicity in the basal forebrain of 6-month-old APP/PS1 mice. GPR139 activation by agonist improved memory and increased the firing and excitability of MS cholinergic neurons in ICV-Aβ mice. Strikingly, the MS provides extensive cholinergic projections to the ventral hippocampal CA3 (vCA3) subregion. Using chemogenetic approaches and 6-/9-month-old APP/PS1 mice, we further showed that inhibiting the MS→vCA3 cholinergic projection disrupted spatial temporal order memory in the early stages of AD, and activation of GPR139 improved memory deficits possibly via the MS→vCA3 cholinergic circuit in the advanced stages. These findings reveal that GPR139 in the MS→vCA3 cholinergic circuit may serve as a critical regulator of cognitive function and offer promising therapeutic strategies for AD.
In vitro bioassays for measuring monoamine transporter function.
Timmerman A, Baumann M, Bosmans F … +2 more , Pottie E, Stove C
Neuropharmacology · 2026 May · PMID 42217750 · Publisher ↗
Monoamine transporters (MATs) - including the dopamine transporter, norepinephrine transporter, and serotonin transporter - are plasma membrane proteins that mediate the uptake of previously released neurotransmitters fr...
Monoamine transporters (MATs) - including the dopamine transporter, norepinephrine transporter, and serotonin transporter - are plasma membrane proteins that mediate the uptake of previously released neurotransmitters from the synaptic cleft, thereby terminating neurotransmitter signaling. MATs are implicated in the pathophysiology of numerous neurological and psychiatric disorders, making them key targets for a wide range of psychotherapeutic agents. Furthermore, stimulant drugs, such as cocaine, methamphetamine, and synthetic cathinones, exert their effects by disrupting normal MAT function. The broad structural and functional diversity of compounds targeting MATs underscores the need for comprehensive in vitro functional characterization. This is essential for elucidating a drug's potency, mechanism of action (e.g., uptake inhibition or efflux induction), and selectivity across MATs. Moreover, certain MAT-modulating compounds can serve as tools to study transporter function itself, furthering the understanding of how MAT-mediated uptake and efflux can be modulated. This review focuses on the in vitro assay techniques most commonly employed to assess MAT activity. More specifically, the review will discuss uptake inhibition and efflux assays that are used to assess MAT function and to study the effects of MAT-modulating compounds. Particular emphasis is placed on the underlying mechanisms of these assays, along with their respective benefits and limitations. Key methodological factors that influence functional outcomes and between-assay comparability are also addressed.
Interactions between SSR504734, a selective glycine transporter type 1 inhibitor, and antiseizure drugs: pharmacodynamic and pharmacokinetic studies in mice.
Gapińska N, Wlaź P, Wyska E … +8 more , Świerczek A, Kamiński K, Jakubiec M, Ciepiela K, Abram M, Latacz G, Poleszak E, Socała K
Neuropharmacology · 2026 May · PMID 42214459 · Publisher ↗
Studies suggest the potential involvement of glycine in seizures and epilepsy; however, no currently available antiseizure medications directly target glycine transporter 1 (GlyT1) or enhance glycinergic neurotransmissio...
Studies suggest the potential involvement of glycine in seizures and epilepsy; however, no currently available antiseizure medications directly target glycine transporter 1 (GlyT1) or enhance glycinergic neurotransmission. Here, we examined the effect of SSR504734, a selective GlyT1 inhibitor, on the protective activity of six antiseizure medications, i.e., lamotrigine and topiramate in the maximal electroshock (MES) seizure test; levetiracetam and carbamazepine in the 6 Hz (32 mA) test; and valproate and ethosuximide in the subcutaneous pentylenetetrazole (scPTZ) test in mice. To evaluate potential pharmacokinetic contributions, plasma and brain concentrations of antiseizure drugs and SSR504734 were measured. In addition, the influence of SSR504734 on recombinant human cytochrome P450 isozymes was assessed. The acute adverse-effect profiles of SSR504734 in combination with the studied drugs were also evaluated. SSR504734 significantly potentiated the antiseizure efficacy of almost all tested antiseizure drugs, with the exception of ethosuximide. The interaction between SSR504734 and levetiracetam was purely pharmacodynamic in nature, as no changes in serum or brain drug concentrations were observed. The enhanced antiseizure activity of topiramate, lamotrigine, and carbamazepine could be partially attributed to pharmacokinetic interactions with SSR504734. At higher doses, SSR504734 administered alone or in combination with antiseizure drugs, induced motor impairments and cognitive deficits. Altogether, these in vivo findings indicate that GlyT1 inhibition may complement the mechanisms of action of diverse antiseizure drugs. Further studies are warranted to evaluate the therapeutic potential of GlyT1 inhibitors, preferably those with improved safety profiles, used alone or as adjunctive therapy with antiseizure medications.
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