Pathological pain: Non-motor manifestations in Parkinson disease and its treatment.

In addition to motor symptoms, non-motor manifestations of Parkinson's disease (PD), i.e. pain, depression, sleep disturbance, and autonomic disorders, have received increasing attention. As one of the non-motor symptoms, pain has a high prevalence and is considered an early pre-motor symptom in the development of PD. In relation to pathological pain and its management in PD, particularly in the early stages, it is hypothesized that the loss of dopaminergic neurons causes a functional deficit in supraspinal structures, leading to an imbalance in endogenous descending modulation. Deficits in dopaminergic-dependent pathways also affect non-dopaminergic neurotransmitter systems that contribute to the pathological processing of nociceptive input, the integration, and modulation of pain in PD. This review examines the onset and progression of pain in PD, with a particular focus on alterations in the central modulation of nociception. The discussion highlights the importance of abnormal endogenous descending facilitation and inhibition in PD pain, which may provide potential clues to a better understanding of the nature of pathological pain and its effective clinical management.

[Neurotrophin-associated mechanisms of delayed-onset muscle soreness: research progress and perspective].

Delayed-onset muscle soreness (DOMS) is a common phenomenon that occurs following a sudden increase in exercise intensity or unfamiliar exercise, significantly affecting athletic performance and efficacy in athletes and fitness individuals. DOMS is characterized by allodynia and hyperalgesia, and their mechanisms remain unclear. Recent studies have reported that neurotrophic factors, such as nerve growth factor (NGF) and glial cell derived neurotrophic factor (GDNF), are involved in the development and maintenance of DOMS. This article provides a review of the research progress on the signaling pathways related to the involvement of NGF and GDNF in DOMS, hoping to provide novel insights into the mechanisms underlying allodynia and hyperalgesia in DOMS, as well as potential targeted treatment.

IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.

Qipengyuania benthica sp. nov. and Qipengyuania profundimaris sp. nov., two novel Erythrobacteraceae members isolated from deep-sea environments.

Two Gram-stain-negative, rod-shaped and non-motile strains, designated as DY56-A-20T and G39T, were isolated from deep-sea sediment of the Pacific Ocean and deep-sea seawater of the Indian Ocean, respectively. Strain DY56-A-20T was found to grow at 15-37 °C (optimum, 28 °C), at pH 6.0-10.0 (optimum, pH 6.5-7.0) and in 0.5-6.0 % (w/v) NaCl (optimum, 1.0-2.0 %), while strain G39T was found to grow at 10-42 °C (optimum, 35-40 °C), at pH 5.5-10.0 (optimum, pH 6.5-7.0) and in 0-12.0 % (w/v) NaCl (optimum, 1.0-2.0 %). The 16S rRNA gene sequence identity analysis indicated that strain DY56-A-20T had the highest sequence identity with Qipengyuania marisflavi KEM-5T (97.6 %), while strain G39T displayed the highest sequence identity with Qipengyuania citrea H150T (98.8 %). The phylogenomic reconstruction indicated that both strains formed independent clades within the genus Qipengyuania. The digital DNA-DNA hybridization and average nucleotide identity values between strains DY56-A-20T/G39T and Qipengyuania/Erythrobacter type strains were 17.8-23.8 % and 70.7-81.1 %, respectively, which are below species delineation thresholds. The genome DNA G+C contents were 65.0 and 63.5 mol% for strains DY56-A-20T and G39T, respectively. The predominant cellular fatty acids (>10 %) of strain DY56-A-20T were C17 : 1 ω6c, summed feature 8 and summed feature 3, and the major cellular fatty acids of strain G39T were C17 : 1 ω6c and summed feature 8. The major polar lipids in both strains were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid and an unidentified polar lipid. The only respiratory quinone present in both strains was ubiquinone-10. Based on those genotypic and phenotypic results, the two strains represent two novel species belonging to the genus Qipengyuania, for which the names Qipengyuania benthica sp. nov. and Qipengyuania profundimaris sp. nov. are proposed. The type strain of Q. benthica is DY56-A-20T (=MCCC M27941T=KCTC 92309T), and the type strain of Q. profundimaris is G39T (=MCCC M30353T=KCTC 8208T).

Fascicle-Selective Ultrasound-Powered Bidirectional Wireless Peripheral Nerve Interface IC.

This paper presents an innovative, minimally invasive, battery-free, wireless, peripheral nervous system (PNS) neural interface, which seamlessly integrates a millimeter-scale, fascicle-selective integrated circuit (IC) with extraneural recording and stimulating channels. The system also incorporates a wearable interrogator equipped with integrated machine-learning capabilities. This PNS interface is specifically tailored for adaptive neuromodulation therapy, targeting individuals with paralysis, amputation, or chronic medical conditions. By employing a neural pathway classifier and temporal interference stimulation, the proposed interface achieves precise deep fascicle selectivity for recording and stimulation without the need for nerve penetration or compression. Ultrasonic energy harvesters facilitate wireless power harvesting and data reception, enhancing the usability of the system. Key circuit performance metrics encompass a 2.2 µVrms input-referred noise, 14-bit ENOB, and a 173 dB Schreier figure of merit (FOM) for the neural analog-to-digital converter (ADC). Additionally, the ultra-low-power radio-frequency (RF) transmitter boasts a remarkable 1.38 pJ/bit energy efficiency. In vivo experiments conducted on rat sciatic nerves provide compelling evidence of the interface's ability to selectively stimulate and record neural fascicles. The proposed PNS neural interface offers alternative treatment options for diagnosing and treating neurological disorders, as well as restoring or repairing neural functions, improving the quality of life for patients with neurological and sensory deficits.

The Utility of Motor Evoked Potential Monitoring for Predicting Postoperative Motor Deficit in Patients With Insular Gliomas.

PURPOSE: Motor evoked potential (MEP) monitoring has been widely applied in various neurosurgical operations. This study aimed to assess the predictive value of MEP monitoring for postoperative motor deficit (PMD) in patients with insular gliomas. METHODS: Demographic and clinical data, MEP monitoring data, and follow-up data of 42 insular glioma patients were retrospectively reviewed, and 40 patients were finally enrolled. The value of MEP monitoring for predicting PMD was assessed with sensitivity, specificity, and false-positive/false-negative rates. Binary multivariate logistic regression analysis was performed to further identify the predictive value of MEP monitoring. RESULTS: Statistical analysis showed that irreversible MEP changes, but not all MEP changes, were more effective in predicting PMD. The sensitivity and specificity of irreversible MEP changes for predicting long-term PMD were 85.71 and 93.94%, whereas the false-positive and -negative rates were 25.00 and 3.12% respectively. In addition, irreversible MEP changes were identified as the only independent predictor for long-term PMD (odds ratio, 101.714; 95% confidence interval, 6.001-1724.122; p = 0.001). CONCLUSIONS: MEP monitoring has been proven to be feasible in insular glioma surgery. Irreversible MEP changes showed good performance in predicting PMD. Their absence can offer an optimistic expectation for the long-term motor outcome. The findings can provide the surgical team with a more effective interpretation of MEP changes and contribute to exploring tailored MEP warning criteria.

[Progress on the mechanism and treatment of Parkinson's disease-related pathological pain].

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms, including bradykinesia, resting tremor, and progressive rigidity. More recently, non-motor symptoms of PD, such as pain, depression and anxiety, and autonomic dysfunction, have attracted increasing attention from scientists and clinicians. As one of non-motor symptoms, pain has high prevalence and early onset feature. Because the mechanism of PD-related pathological pain is unclear, the clinical therapy for treating PD-related pathological pain is very limited, with a focus on relieving the symptoms. This paper reviewed the clinical features, pathogenesis, and therapeutic strategies of PD-related pathological pain and discussed the mechanism of the chronicity of PD-related pathological pain, hoping to provide useful data for the study of drugs and clinical intervention for PD-related pathological pain.

Sex-related correspondence between mechanical hypersensitivity and the discharge of medullary pain control neurons in neuropathic rats.

Here we studied whether the sex-related difference in mechanical hypersensitivity induced by neuropathy is associated with the discharge rate of medullary pain control neurons. We performed experiments in male and female rats with spared nerve injury (SNI) model of peripheral neuropathy. Mechanical hypersensitivity was assessed behaviorally by monofilaments. Discharge rates of pain-control neurons were determined using in vivo single unit recordings under light anesthesia. Recording targets were two medullary nuclei involved in descending pain control: the rostral ventromedial medulla (RVM) and the medullary dorsal reticular nucleus (DRt). Based on the response to peripheral noxious stimulus, neurons were classified as pronociceptive RVM ON-like or DRt neurons, or antinociceptive RVM OFF-like neurons. Behavioral results indicated that the mechanical hypersensitivity induced by SNI was significantly stronger in females than males. The ongoing discharge rates of pronociceptive RVM ON-like neurons were higher and those of antinociceptive RVM OFF-like neurons lower in SNI females than SNI males. Ongoing discharge rates of pronociceptive DRt neurons were not significantly different between SNI females and males. The results suggest that a sex difference in the discharge rate of pain control neurons in the RVM but not DRt may contribute to the maintenance of stronger neuropathic hypersensitivity in females.

Floral trait variation across individual plants within a population enhances defense capability to nectar robbing.

Floral trait variation may help pollinators and nectar robbers identify their target plants and, thus, lead to differential selection pressure for defense capability against floral antagonists. However, the effect of floral trait variation among individuals within a population on multi-dimensional plant-animal interactions has been little explored. We investigated floral trait variation, pollination, and nectar robbing among individual plants in a population of the bumble bee-pollinated plant, Caryopteris divaricata, from which flowers are also robbed by bumble bees with varying intensity across individuals. We measured the variation in corolla tube length, nectar volume and sugar concentration among individual plants, and evaluated whether the variation were recognized by pollinators and robbers. We investigated the influence of nectar robbing on legitimate visitation and seed production per fruit. We found that the primary nectar robber (Bombus nobilis) preferred to forage on plants with long-tubed flowers, which produced less nectar and had lower sugar concentration compared to those with shorter corolla tubes. Individuals with shorter corolla tubes had comparatively lower nectar robbing intensity but higher visitation by legitimate visitors (mainly B. picipes) and higher seed production. Nectar robbing significantly reduced seed production because it decreased pollinator visits. However, neither pollination nor seed production differed between plants with long and short corolla tubes when nectar robbers were excluded. This finding suggests that floral trait variation might not be driven by pollinators. Such variation among individual plants thus allows legitimate visitors and nectar robbers to segregate niches and enhances population defense against nectar robbing in unpredictable conditions.

Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages.

PURPOSE: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state. EXPERIMENTAL DESIGN: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. RESULTS: We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. CONCLUSIONS: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.

Application of intraoperative evoked potential monitoring in patients with anterior cerebral artery aneurysms.

OBJECTIVES: The location of the aneurysm can affect the relationship between changes in intraoperative neurophysiological monitoring indicators and postoperative outcomes. The current study aimed to evaluate the application value of motor evoked potential and somatosensory evoked potential monitoring in anterior cerebral artery aneurysm surgery. METHODS: The data of 219 patients with anterior cerebral artery aneurysms treated via surgical clipping were retrospectively reviewed. The correlation of motor/somatosensory evoked potential monitoring with postoperative motor dysfunction was assessed using false positive rate, false negative rate, sensitivity, and specificity. Binary multivariate logistic regression analysis was applied to identify potential predictors for postoperative motor dysfunction. RESULTS: Motor evoked potential monitoring showed satisfactory effectiveness in predicting postoperative motor dysfunction (Sensitivity, 60.00%; Specificity, 85.43%; False positive rate, 14.57%; False negative rate, 40%). While somatosensory evoked potential did not (Sensitivity, 15.00%; Specificity, 96.98%; False positive rate, 3.02%; False negative rate, 85%). Abnormal motor evoked potential was identified as the only independent predictor for both short-term (odds ratio, 8.893; 95% confidence interval, 2.749-28.773; p<0.001) and long-term postoperative motor dysfunction (odds ratio, 7.877; 95% confidence interval, 2.144-28.945; p=0.002). CONCLUSIONS: During intraoperative neurophysiological monitoring for patients with anterior cerebral artery aneurysms, paying more attention to motor evoked potential changes was a reasonable choice. And somatosensory evoked potential monitoring can serve as an auxiliary reference.

Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD.

Influences of Friedel's Salt Produced by CaO-Activated Titanium-Extracted Tailing Slag on Chloride Binding.

Titanium-extracted tailing slag (TETS) has high activity, but the content of chloride ions is high. To effectively bind the chloride ions, CaO was used to activate the TETS, and the solidified cementitious material of CaO-activated TETS was prepared. The effects of CaO content and curing age on the strength of solidified samples, chloride binding capacity, and chloride binding mechanism were studied. By means of XRD, FTIR, SEM, and EDS, the hydration reaction products, microstructure, morphology, and micro-components of the solidified sample were characterized. The results show that the chloride ions can be effectively bound by using CaO to activate TETS with higher mechanical strength. When the CaO content is 10 wt%, the strength of the 28-day-cured body can reach more than 20 MPa, the chloride ion binding amount is 38.93 mg/g, and the chloride binding rate is as high as 68%. The new product phases of the solidified sample are mainly Friedel's salt (FS) and calcite, in which the amount of FS production and the degree of crystal development are affected by the CaO content and curing age. The chloride binding ions in the solidified sample are mainly the chemical binding by FS. The FS diffraction peak strength increases with the increase of CaO content and curing age, but the calcite diffraction peak strength is less affected by them. FS mainly accumulates and grows in the pores of the solidified sample. It can optimize the pore structure of the solidified sample and improve the strength of the solidified sample while binding chloride ions. The results can provide useful information for the resource utilization of chlorine-containing TETS, the improvement of durability of Marine concrete, and the application of sea sand in concrete.

Sterol regulatory element-binding protein 2 maintains glioblastoma stem cells by keeping the balance between cholesterol biosynthesis and uptake.

BACKGROUND: Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptors. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies. METHODS: In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptors in GSCs. RESULTS: Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than in invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient conditions. CONCLUSIONS: SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.

Three-dimensional impact-angle-constrained cooperative guidance strategy against maneuvering target.

In order to improve the multiple-missile cooperative attack capability and penetration capability, this paper investigates two three-dimensional impact-angle-constrained cooperative guidance strategies against maneuvering target for controllable thrust missiles. First, a three-dimensional nonlinear guidance model is established that does not assume small missile lead angles in the guidance process. Second, in the line-of-sight (LOS) direction of the cluster cooperative guidance strategy, the proposed guidance algorithm transforms the simultaneous attack problem into a second-order multiagent consensus problem, which effectively solves the practical problem of low guidance precision provoked by the time-to-go estimation. Then, by combining second-order sliding mode control (SMC) and nonsingular terminal SMC theory, the guidance algorithms in the normal and lateral directions to the LOS are designed, respectively, so that the multi-missile can accurately attack a maneuvering target while satisfying the impact angle constraints. Finally, by utilizing the second-order multiagent consensus tracking control in the leader-following cooperative guidance strategy, a novel leader-following time consistency algorithm is investigated to ensure that the leader and followers can attack the maneuvering target simultaneously. Moreover, the stability of the investigated guidance algorithms is proved mathematically. The effectiveness and superiority of the proposed cooperative guidance strategies are verified by numerical simulations.

High n-type and p-type conductivities and power factors achieved in a single conjugated polymer.

The charge transport properties of conjugated polymers are commonly limited by the energetic disorder. Recently, several amorphous conjugated polymers with planar backbone conformations and low energetic disorder have been investigated for applications in field-effect transistors and thermoelectrics. However, there is a lack of strategy to finely tune the interchain π-π contacts of these polymers that severely restricts the energetic disorder of interchain charge transport. Here, we demonstrate that it is feasible to achieve excellent conductivity and thermoelectric performance in polymers based on thiophene-fused benzodifurandione oligo(p-phenylenevinylene) through reducing the crystallization rate of side chains and, in this way, carefully controlling the degree of interchain π-π contacts. N-type (p-type) conductivities of more than 100 S cm-1 (400 S cm-1) and power factors of more than 200 µW m-1 K-2 (100 µW m-1 K-2) were achieved within a single polymer doped by different dopants. It further demonstrated the state-of-the-art power output of the first flexible single-polymer thermoelectric generator.

Correction: Identification of Hybrids in Potamogeton: Incongruence between Plastid and ITS Regions Solved by a Novel Barcoding Marker PHYB.

[This corrects the article DOI: 10.1371/journal.pone.0166177.].

[Temporal and Spatial Variation Characteristics of Carbon Storage in the Source Region of the Yellow River Based on InVEST and GeoSoS-FLUS Models and Its Response to Different Future Scenarios].

Regional land use change is the main cause of carbon storage changes in ecosystems. Predicting the impact of future land use changes on carbon storage is of great significance for the sustainable development of carbon storage functions. In recent years, under the combined action of natural and human factors, the land use in the source region of the Yellow River has changed significantly, and its carbon storage function has also changed accordingly. This study combined InVEST and GeoSoS-FLUS models to evaluate land use change and its impact on carbon storage in the source region of the Yellow River from 2000 to 2020 and from 2020 to 2040 under different scenarios. The results showed that:① from 2000 to 2020, the carbon storage in the source region of the Yellow River showed an overall upward trend, with a total increase of 11.59×106 t. ② Over the past 20 years, the land use changes in the source region of the Yellow River included mainly the increase in the area of low-coverage grassland, construction land, and wetland and the decrease in the area of high-coverage grassland, medium-coverage grassland, and unused land, as well as the large-scale reduction of unused land and the reduction of grassland. The increase in the area of wetlands was the main reason for the increase in carbon storage. ③ Under the natural change scenario in 2040, the ecosystem carbon storage in the source region of the Yellow River was 871.34×106 t, an increase of 3.92×106 t compared with that in 2020. Under the ecological protection scenario, carbon storage increased significantly, with an increase of 13.53×106 t compared with that in 2020. The results of this study can provide a scientific reference for the decision-making of land use management and the sustainable development of carbon storage function in the source region of the Yellow River.

Reduced mechanical hypersensitivity by inhibition of the amygdala in experimental neuropathy: Sexually dimorphic contribution of spinal neurotransmitter receptors.

Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male and female rats with spared nerve injury (SNI) model of neuropathy. SNI induced mechanical hypersensitivity that was stronger in females. Reversible blocking of the CeA with muscimol (GABAA receptor agonist) induced a reduction of mechanical hypersensitivity that did not differ between males and females. Following spinal co-administration of atipamezole (α2-adrenoceptor antagonist), the reduction of mechanical hypersensitivity by CeA muscimol was attenuated more in males than females. In contrast, following spinal co-administration of raclopride (dopamine D2 receptor antagonist) the reduction of hypersensitivity by CeA muscimol was attenuated more in females than males. The reduction of mechanical hypersensitivity by CeA muscimol was equally attenuated in males and females by spinal co-administration of WAY-100635 (5-HT1A receptor antagonist) or bicuculline (GABAA receptor antagonist). The CeA muscimol induced attenuation of ongoing pain-like behavior (conditioned place preference test) that was reversed by spinal co-administration of atipamezole in both sexes. The results support the hypothesis that CeA contributes to mechanical hypersensitivity and ongoing pain-like behavior in SNI males and females. Disinhibition of descending controls acting on spinal α2-adrenoceptors, 5-HT1A, dopamine D2 and GABAA receptors provides a plausible explanation for the reduction of mechanical hypersensitivity by CeA block in SNI. The involvement of spinal dopamine D2 receptors and α2-adrenoceptors in the CeA muscimol-induced reduction of mechanical hypersensitivity is sexually dimorphic, unlike that of spinal α2-adrenoceptors in the reduction of ongoing neuropathic pain.