Neuropharmacology最新文献

Empathy is the capacity to understand and share the experiences of others. This ability fosters connections between individuals, enriching the fabric of our shared world. One notable example is empathy for the pain of others. Such experiences facilitate the identification of potential dangers, both for oneself and for others. Neuroimaging studies have helped to pinpoint brain regions that modulate empathic pain. Recently, there has also been a surge in studies exploring the neural mechanisms of empathic pain in rodent models. Neuropsychiatric disorders such as autism, psychosis, and schizophrenia often exhibit empathy deficits. Targeting the modulation of empathic pain holds potential for alleviating core symptoms in these patients. Interestingly, empathy research may also benefit pain management, leading to new approaches for understanding the negative emotions associated with pain. This review summarizes recent advances in neuroimaging for the study of empathic pain, outlines the underlying neurocircuit mechanisms, describes therapeutic strategies, and explores promising avenues for future research. This article is part of the Special Issue on "Empathic Pain".

The primary objective of the present study is to provide further evidence that the endogenous S-nitrosothiol, S-nitroso-L-cysteine (L-CSNO), plays an essential role in signaling the hypoxic ventilatory response (HVR) in rodents. Key findings were that (1) injection of L-CSNO (50 nmol/kg, IV) caused a pronounced increase in frequency of breathing (Freq), tidal volume (TV) and minute ventilation (MV) in naïve C57BL/6 mice, whereas injection of D-CSNO (50 nmol/kg, IV) elicited minimal responses; (2) L-CSNO elicited minor responses in (a) C57BL/6 mice with bilateral carotid sinus nerve transection (CSNX), (b) C57BL/6 mice treated neonatally with capsaicin (CAP) to eliminate small-diameter C-fibers, and (c) C57BL/6 mice receiving continuous infusion of L-CSNO receptor antagonists, S-methyl-L-cysteine and S-ethyl-L-cysteine (L-SMC + L-SEC, both at 5 μmol/kg/min, IV); and (3) injection of S-nitroso-L-glutathione (L-GSNO, 50 nmol/kg, IV) elicited pronounced ventilatory responses that were not inhibited by L-SMC + L-SEC. Subsequent exposure of naïve C57BL/6 mice to a hypoxic gas challenge (HXC; 10% O₂, 90% N₂) elicited pronounced increases in Freq, TV and MV that were subject to roll-off. These HXC responses were markedly reduced in CSNX, CAP, and L-SMC + L-SEC-infused C57BL/6 mice. Subsequent exposure of all C57BL/6 mice (naïve, CSNX, CAP, and L-SMC + L-SEC) to a hypercapnic gas challenge (5% CO₂, 21% O₂, 74% N₂) elicited similar robust increases in Freq, TV and MV. Taken together, these findings provide evidence that an endogenous factor with pharmacodynamic properties similar to those of L-CSNO, rather than L-GSNO, mediates the HVR in male C57BL/6 mice.

Environmental changes may alter gene expression in depression and anxiety disorders through epigenetic regulation, including via small non-coding RNAs (sncRNAs) and their major subclass, microRNAs (miRNAs). However, underlying mechanisms mediating miRNA regulation in response to changing environmental stimuli are unclear. Using the serotonin transporter (5-HTT) knockout (KO) mouse model of depression/anxiety, this study aimed to compare the effects of voluntary exercise (EX) versus chronic treatment with the stress hormone corticosterone (CT), on hippocampal miRNA transcriptome and proteome in five comparison groups: WT-SH vs. KO-SH; WT-SH vs. WT-EX; KO-SH vs. KO-EX; WT-SH vs. WT-CT; KO-SH vs. KO-CT. We hypothesized that treatment with stress hormone will result in miRNA and proteomics changes observed in genetic model of depression, while exercise will have beneficial effects similar to antidepressant treatment. Using high-throughput sequencing of miRNAs and mass spectrometry (MS)-based approaches for protein expression, we revealed 337 differentially expressed (DE) miRNAs and 67 proteins in 5-HTT KO mice compared to wild-type (WT) control mice in standard-housing conditions. After exercise, there were 200 DE miRNAs and 3 DE proteins in WT mice, and 20 DE miRNAs and 95 DE proteins in 5-HTT KO mice, while corticosterone treatment led to 168 DE miRNAs and 1 DE protein in WT, and 21 DE miRNAs and 21 DE proteins in 5-HTT KO mice. Serotonergic dysfunction (due to the 5-HTT KO gene mutation) induced altered expression of miRNAs and proteins involved in regulation of neurodevelopment, neurogenesis and neuroinflammatory responses. Treatment with the stress hormone corticosterone in WT mice activated pathways which were also found altered in 5-HTT KO mice, while exercise caused antidepressant-like effects. These findings suggest that functional 5-HTT might be required for the beneficial effects of exercise on miRNA expression. Our study is the first to explore how gene-environment interactions affect miRNA/proteomic composition in a mouse model of depression/anxiety, and extends our understanding of gene-environmental interactions underlying these affective disorders.

This study aims to investigate whether androgen deprivation, simulating conditions of aging or disease-induced low testosterone levels, increases the susceptibility of male mice to sevoflurane neurotoxicity, and whether testosterone supplementation can reverse the toxic effects of sevoflurane. In here, young male mice were subjected to orchiectomy (ORC) to induce testosterone deprivation. Various techniques, including western blotting, immunofluorescence, Morris Water Maze, Golgi staining, and neuronal signal measurement, were used to evaluate the effects of sevoflurane on long-term (ORC 10 weeks) and short-term (ORC 2 weeks) testosterone deprivation, and assess whether testosterone (1 mg/kg 1 h before sevoflurane exposure) could mitigate sevoflurane-induced neurotoxicity. Flutamide and anastrozole were administered to study testosterone's pathways of action. We found that sevoflurane increased tau phosphorylation and decreased the transient amplitude of Ca²⁺ signals and dendritic spine density in dorsal hippocampal CA1 (dCA1) neurons, leading to cognitive impairment in testosterone-deprived male mice. Testosterone treatment reversed the effects of sevoflurane in short-term testosterone-deprived male mice, but not in long-term testosterone-deprived male mice. Additionally, the neuroprotective effect of testosterone was blocked by flutamide rather than anastrozole. We have discovered for the first time that testosterone can mitigate the sevoflurane-induced neurotoxicity in testosterone-deprived male mice and that there exists a therapeutic time window, which may be mediated by androgen receptors. This may provide new insights into the neuroprotective role of sex hormones.

The affective dimension in postsurgical pain is still poorly understood. Since neuropeptide oxytocin (OXT) has been implicated in a broad spectrum of pain and negative emotion, we investigated the potential therapeutic effect of intranasal OXT on postsurgical pain and associated anxiety in a mice model of plantar incision. The role of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels was explored by using behavioral pharmacology experiments. We reported that plantar incision in mice induced anxiety-like behaviors and mechanical pain hypersensitivity, with a concurrent decrease of the oxytocin receptor (OTR) in the hippocampus. The immunofluorescence staining showed that the OTR were enriched in pyramidal neurons in CA3 subregion of hippocampus and which were highly co-expressed with the BK(Ca) channels in CA3 subregion. Intranasal OXT significantly ameliorated this postsurgical pain and associated anxiety in a dose-dependent manner, while Intra-CA3 microinjection of OTR antagonist atosiban or the BK(Ca) channel blocker paxilline reduced the effect of OXT in incisional mice. Moreover, intra-CA3 microinjection of BK(Ca) channel opener NS1619 produced a similar effect on postsurgical pain and associated anxiety-like behaviors as those observed following intranasal OXT administration. Conversely, intra-CA3 microinjection of BK(Ca) channel blocker paxilline in normal mice was sufficient to evoke mechanical pain hypersensitivity. Taken together, our data suggested that intranasal OXT administration exerted analgesic and anxiolytic effects in incisional mice by opening BK(Ca) channels in the CA3 subregion of hippocampus.

Ageing is one of the most important risk factors for chronic health conditions, including neurodegenerative diseases. Inflammation is a feature of ageing, as well as a key pathophysiological mechanism for degenerative diseases. Microglia play multiple roles in the central nervous system; their states entail a complex assemblage of responses reflecting the multiplicity of functions they fulfil both under homeostatic basal conditions and in response to stimuli. Whereas glial cells can promote neuronal homeostasis and limit neurodegeneration, age-related inflammation (i.e. inflammaging) leads to the functional impairment of microglia and astrocytes, exacerbating their response to stimuli. Thus, microglia are key mediators for age-dependent changes of the nervous system, participating in the generation of a less supportive or even hostile environment for neurons. Whereas multiple changes of ageing microglia have been described, here we will focus on the neuron-microglia regulatory crosstalk through fractalkine (CX3CL1) and CD200, and the regulatory cytokine Transforming Growth Factor β1 (TGFβ1), which is involved in immunomodulation and neuroprotection. Ageing results in a dysregulated activation of microglia, affecting neuronal survival, and function. The apparent unresponsiveness of aged microglia to regulatory signals could reflect a restriction in the mechanisms underlying their homeostatic and reactive states. The spectrum of functions, required to respond to life-long needs for brain maintenance and in response to disease, would progressively narrow, preventing microglia from maintaining their protective functions. This article is part of the Special Issue on "Microglia".

Cannabinoid CB₂ agonists show promise as analgesics because they lack unwanted side effects associated with direct activation of CB₁ receptors. CB₂ receptor activation suppresses pathological pain in animal models, but the types of pain that best respond to CB₂ agonists are incompletely understood. This gap in knowledge may contribute to failures in clinical translation. We previously showed that the G protein-biased CB₂ receptor agonist LY2828360 attenuated the maintenance of neuropathic pain behavior in mouse models of inflammatory and neuropathic pain. Whether this finding generalizes to neuropathic pain induced by traumatic nerve injury or occurs in multiple rodent species remains unknown. Here we show that LY2828360 (3 and 10 mg/kg i.p.), administered acutely, reversed paclitaxel-induced mechanical hypersensitivity in male rats. By contrast, LY2828360 (10 mg/kg i.p.), administered acutely, attenuated mechanical hypersensitivity in a spared nerve injury (SNI) rat model, whereas the low dose (3 mg/kg i.p.) was ineffective. In both models, efficacy of LY2828360 was sustained following 10 days of repeated dosing. LY2828360 (3 mg/kg i.p.) also prevented development of tolerance to the opioid analgesic morphine (6 mg/kg i.p.) in rats with SNI when co-administered. LY2828360 (3 mg/kg i.p.) did not produce preference or aversion in the conditioned place preference (CPP) test in rats when administered alone but blocked CPP to morphine (6 mg/kg i.p.). Lastly, LY2828360 (3 mg/kg i.p.) did not alter the acquisition of i.v. morphine self-administration under fixed ratio 1 (FR1) and 3 (FR3) or motivation to work for morphine under a progressive ratio (PR) schedule of reinforcement.

Background: Autism spectrum disorder (ASD) is a lifelong condition. It is characterized by complex etiologies, including disruptions in exogenous retinoic acid (RA) signaling, which may serve as an environmental risk factor. Targeting the RA pathway presents a promising therapeutic avenue, though the precise mechanisms remain to be elucidated.

Methods: Female Sprague-Dawley rats were treated with valproic acid (VPA) during pregnancy to induce an ASD model in their offspring. Some offspring received RA treatment postnatally. Social behavior and brain-functional connectivity were assessed using behavioral tests and functional magnetic resonance imaging (fMRI), respectively. Transcriptomics analysis and proteomics analysis of the hypothalamus identified differentially expressed genes (DEGs) and differentially expressed proteins (DEPs). These were intersected with ASD pathogenic genes (APGs) and ASD pathogenic proteins (APPs) to identify differentially expressed APGs (DE-APGs) and differentially expressed APPs (DE-APPs), which were validated by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Analyses of enrichment of signaling pathways were done using the Kyoto Encyclopedia of Genes and Genomes database.

Results: RA treatment significantly improved social behaviors and revealed distinct patterns of hypo- and hyper-connectivity across various brain regions, with notable changes involving the hypothalamus and facial nerve. Differential analysis revealed 4165 DEGs (DEG 1) and 329 DEPs (DEP 1) between control and VPA groups, and 1610 DEGs (DEG 2) and 197 DEPs (DEP 2) between VPA and RA supplementation (RAS) groups. Twenty-two DE-APGs and five DE-APPs were identified, with key associations found between proteins such as Tbl1xr1 and Myo5a and >13 genes including Nrxn1, Cacna1e, and Gabrb2. Significant alterations in DE-APGs, including Grin2b, Nrxn1, Cacna1e, and Gabrb2, were confirmed via real-time RT-PCR and western blotting. In addition, 22 key signaling pathways were enriched in DEPs and DEGs.

Conclusion: RA supplementation in ASD rats induced by VPA may ameliorate social deficits and modulated functional connectivity, especially in the hypothalamus and facial nerve regions. This suggests potential therapeutic benefits for neural circuitry dysregulation in ASD. Additionally, RA altered critical gene and protein expressions in hypothalamus, implicating its role in modulating key signaling pathways to mitigate social deficits in ASD. This study provides new insights into the molecular mechanisms of ASD and supports the development of novel therapeutic strategies.

Background: The opioid epidemic is leading to increased opioid use in adolescent populations. A growing body of evidence suggests that taking opioids during adolescence can disrupt normal development and impact future offspring. This study investigates the impact of paternal morphine exposure during adolescence on the hypothalamic-pituitary-adrenal (HPA) axis and release of endorphins in the offspring.

Methods: Male rats were administered morphine once a day from postnatal day (PND)30-39 using an increasing dosing regimen (5-25 mg/kg/day increasing every other day). They were mated during adulthood to drug naïve females. Their offspring were assessed for circulating beta-endorphin (βE) and corticosterone levels on PND30 (a timepoint prior to puberty in both sexes) in response to an acute injection of saline, oxycodone (1 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.). At PND60, naïve littermates were catheterized so that a within-subjects design could be implemented to measure βE and corticosterone in response to saline, oxycodone, or cocaine.

Results: In males, βE levels in the plasma were increased in Mor-F1 males compared to Sal-F1 males regardless of the acute injection. This elevation was observed at PND30 and PND60. There were no differences in female circulating βE. In terms of corticosterone, male Mor-F1 offspring had blunted corticosterone at PND30, but elevated corticosterone in response to oxycodone at PND60. The females also tended towards lower corticosterone prior to puberty but had significantly elevated levels of circulating corticosterone following an acute cocaine injection.

Conclusion: Paternal morphine exposure during adolescence induces sex- and drug-specific changes in secreted hormone responses in offspring. The alterations in βE and corticosterone levels suggest mechanisms through which adolescent opioid exposure can impact endocrine functions of future offspring. These findings contribute to the understanding of intergenerational transmission of substance use effects.

Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model in male and female mice to assess changes in locomotor responses after repeated cocaine (10 mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.