Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain.

Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC α-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7±2.7% and 55.0±3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9±1.9% to 33.5±0.7% (p<0.01) and the total Nedd4-2 protein to 44%±0.13% of its basal level (p<0.01, n=4 animals in each group, mean±SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries.

Etude de l'activation et de l'inactivation pH-dépendantes des canaux ASICs (Acide-Sensing Ion Channels)

RESUME: Etude de l'activation et de l'inactivation pH-dépendantes des canaux ASICs (Acid-Sensing Ion Channels) Benoîte BARGETON, Département de Pharmacologie et de Toxicologie, Université de Lausanne, rue du Bugnon 27, CH-1005 Lausanne, Suisse Les canaux sodiques ASICs (Acid-Sensing Ion Channels) participent à la signalisation neuronale dans les systèmes nerveux périphérique et central. Ces canaux non voltage dépendants sont impliqués dans l'apprentissage, l'expression de la peur, la neurodégénération consécutive à une attaque cérébrale et la douleur. Les bases moléculaires sous-tendant leur activité ne sont pas encore totalement comprises. Ces canaux sont activés par une acidification du milieu extracellulaire et régulés, entre autres, par des ions tels que le Ca2+, le Zn2+ et le CI". La cristallisation de ASIC inactivé a été publiée. Le canal est un trimére de sous-unités identiques ou homologues. Chaque sous-unité a été décrite en analogie à un avant bras, un poignet et une main constituée d'un pouce, d'un doigt, d'une articulation, une boule β et une paume. Nous avons appliqué une approche bioinformatique systématique pour identifier les pH senseurs putatifs de ASICIa. Le rôle des pH senseurs putatifs a été testé par mutagénèse dirigée et des modifications chimiques combinées à une analyse fonctionnelle afin de comprendre comment les variations de ρ H ouvrent ces canaux. Les pH senseurs sont des acides aspartiques et glutamiques éparpillés sur la boucle extracellulaire suggérant que les changements de pH contrôlent l'activation et l'inactivation de ASIC en (dé)protonant ces résidus en divers endroits de la protéine. Par exemple lors de l'activation, la protonation des résidus à l'interface entre le pouce, la boule β et le doigt d'une même sous-unité induit un mouvement du pouce vers la bouie β et le doigt. De même lors de l'inactivation du canal les paumes des trois sous-unités formant une cavité se rapprochent. D'après notre approche bioinformatique, aucune histidine n'est impliquée dans la détection des variations de pH extracellulaire c'est-à-dire qu'aucune histidine ne serait un pH-senseur. Deux histidines de ASIC2a lient le Zn2+ et modifient l'affinité apparente du canal pour les protons. Une seule des deux est conservée parmi tous les ASICs, hASICIa H163. Elle forme un réseau de liaison hydrogène avec ses voisins conservés. L'étude détaillée de ce domaine, Pinterzone, montre son importance dans l'expression fonctionnelle des canaux. La perturbation de ce réseau par l'introduction d'un résidu hydrophobe (cystéine) par mutagénèse dirigée diminue l'expression du canal à la membrane plasmique. La modification des cystéines introduites par des réactifs spécifiques aux groupements sulfhydryle inhibe les canaux mutés en diminuant leur probabilité d'ouverture. Ces travaux décrivent les effets de l'acidification du milieu extracellulaire sur les canaux ASICs. ABSTRACT: Study of pH-dependent activation and inactivation of ASIC channels Benoîte BARGETON, Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1G05 Lausanne, Switzerland The ASIC (Acid-Sensing Ion Channels) sodium channels are involved in neuronal signaling in the central and peripheral nervous system. These non-voltage-gated channels are involved in learning, the expression of fear, neurodegeneration after ischemia and pain sensation. The molecular bases underlying their activity are not yet fully understood. ASICs are activated by extracellular acidification and regulated, eg by ions such as Ca2+, the Zn2+ and CI". The crystallization of inactivated ASIC has been published. The channel is a trimer of identical or homologous subunits. Each subunit has been described in analogy to a forearm, wrist and hand consisting of a thumb, a finger, a knuckle, a β-ball and a palm. We applied a systematic computational approach to identify putative pH sensor(s) of ASICIa. The role of putative pH sensors has been tested by site-directed mutagenesis and chemical modification combined with functional analysis in order to understand how changes in pH open these channels. The pH sensors are aspartic and glutamic acids distributed throughout the extracellular loop, suggesting that changes in pH control activation and inactivation of ASIC by protonation / deprotonation of many residues in different parts of the protein. During activation the protonation of various residues at the interface between the finger, the thumb and the β-ball induces the movement of the thumb toward the finger and the β-ball. During inactivation of the channel the palms of the three subunits forming a cavity approach each other. No histidine has been shown to be involved in extracellular pH changes detection, i.e. no histidine is a pH- sensor. Two histidines of ASIC2 bind Zn2+ and alter the apparent affinity of channel for protons. Only one of the two His is conserved among all ASICs, hASICIa H163. This residue is part of a network of hydrogen bonding with its conserved neighbors. The detailed study of this area, the interzone, shows its importance in the functional expression of ASICs. Disturbance of this network by the introduction of hydrophobic residues decreases the cell surface channel expression. Chemical modification of the introduced cysteines by thiol reactive compounds inhibits the mutated channels by a reduction of their open probability. These studies describe the effects of extracellular acidification on ASICs. RESUME GRAND PUBLIC: Etude de l'activation et de l'inactivation pH-dépendantes des canaux ASICs (Acid-Sensing Ion Channels) Benoîte BARGETON, Département de Pharmacologie et de Toxicologie, Université de Lausanne, rue du Bugnon 27, CH-1005 Lausanne, Suisse La transmission synaptique est un processus chimique entre deux neurones impliquant des neurotransmetteurs et leurs récepteurs. Un dysfonctionnement de certains types de synapses est à l'origine de beaucoup de troubles nerveux, tels que certaine forme d'épilepsie et de l'attention. Les récepteurs des neurotransmetteurs sont de très bonnes cibles thérapeutiques dans de nombreuses neuropathologies. Les canaux ASICs sont impliqués dans la neurodégénération consécutive à une attaque cérébrale et les bloquer pourraient permettre aux patients d'avoir moins de séquelles. Les canaux ASICs sont des détecteurs de l'acidité qui apparaît lors de situations pathologiques comme l'ischémie et l'inflammation. Ces canaux sont également impliqués dans des douleurs. Cibler spécifiquement ces canaux permettrait d'avoir de nouveaux outils thérapeutiques car à l'heure actuelle l'inhibiteur de choix, l'amiloride, bloque beaucoup d'autres canaux empêchant son utilisation pour bloquer les ASICs. C'est pourquoi il faut connaître et comprendre les bases moléculaires du fonctionnement de ces récepteurs. Les ASICs formés de trois sous-unités détectent les variations de l'acidité puis s'ouvrent transitoirement pour laisser entrer des ions chargés positivement dans la cellule ce qui active la signalisation neuronale. Afin de comprendre les bases moléculaires de l'activité des ASICs nous avons déterminé les sites de liaison des protons (pH-senseurs), ligands naturels des ASICs et décrit une zone importante pour l'expression fonctionnelle de ces canaux. Grâce à une validation systématique de résultats obtenus en collaboration avec l'Institut Suisse de Bioinformatique, nous avons décrit les pH-senseurs de ASICIa. Ces résultats, combinés à ceux d'autres groupes de recherche, nous ont permis de mieux comprendre comment les ASICs sont ouverts par une acidification du milieu extracellulaire. Une seconde étude souligne le rôle structural crucial d'une région conservée parmi tous les canaux ASICs : y toucher c'est diminuer l'activité de la protéine. Ce domaine permet l'harmonisation des changements dus à l'acidification du milieu extracellulaire au sein d'une même sous-unité c'est-à-dire qu'elle participe à l'induction de l'inactivation due à l'activation du canal Cette étude décrit donc quelle région de la protéine atteindre pour la bloquer efficacement en faisant une cible thérapeutique de choix.

Nanosized Nb-TiO2 gas sensors derived from alkoxides hydrolization

Nanocrystalline TiO2 modified with Nb has been produced through the sol-gel technique. Nanopowders have been obtained by means of the hydrolysis of pure alkoxides with deionized water and peptization of the resulting hydrolysate with diluted acid nitric at 100 C. The addition of Nb stabilizes the anatase phase to higher temperatures. XRD spectra of the undoped and the Nb-doped samples show that the undoped sample has been almost totally converted to rutile at 600 C, meanwhile the doped samples present still a low percentage of rutile phase. Nanocrystalline powders stabilized at 600 C with grain sizes of about 17 nm have successfully been synthesized by the addition of Nb with a concentration of 2% at., which appears to be an adequate additive concentration to improve the gas sensor performances, such as it is suggested by the catalytic conversion efficiency experiments performed from FTIR measurements. FTIR absorbance spectra show that catalytic conversion of CO occurs at lower temperatures when niobium is introduced. The electrical response of the films to different concentrations of CO and ethanol has been monitored in dry and wet environments in order to test the influence of humidity in the sensor response. The addition of Nb decreases the working temperature and increases the stability of the layers. Also, large enhancement of the response time is obtained even with lower working temperatures. Moreover, humidity effects on the gas sensor response toward CO and ethanol are less important in Nb-doped samples than in the undoped ones.

Size-dependent recombination dynamics in ZnO nanowires.

A deep understanding of the recombination dynamics of ZnO nanowires NWs is a natural step for a precise design of on-demand nanostructures based on this material system. In this work we investigate the influence of finite-size on the recombination dynamics of the neutral bound exciton around 3.365 eV for ZnO NWs with different diameters. We demonstrate that the lifetime of this excitonic transition decreases with increasing the surface-to-volume ratio due to a surface induced recombination process. Furthermore, we have observed two broad transitions around 3.341 and 3.314 eV, which were identified as surface states by studying the dependence of their life time and intensitiy with the NWs dimensions.

Aggregate stability as affected by short and long-term tillage systems and nutrient sources of a hapludox in southern Brazil

The ability of a soil to keep its structure under the erosive action of water is usually high in natural conditions and decreases under frequent and intensive cultivation. The effect of five tillage systems (NT = no-till; CP = chisel plowing and one secondary disking; CT = primary and two secondary distings; CTb = CT with crop residue burning; and CTr = CT with removal of crop residues from the field), combined with five nutrient sources (C = control, no nutrient application; MF = mineral fertilizers according to technical recommendations for each crop; PL = 5 Mg ha-1 y-1 fresh matter of poultry litter; CM = 60 m³ ha-1 y-1 slurry cattle manure; and SM = 40 m³ ha-1 y-1 slurry swine manure) on wet-aggregate stability was determined after nine years (four sampled soil layers) and on five sampling dates in the 10th year (two sampled soil layers) of the experiment. The size distribution of the air-dried aggregates was strongly affected by soil bulk density, and greater values of geometric mean diameter (GMD AD) found in some soil tillage or layer may be partly due to the higher compaction degree. After nine years, the GMD AD on the surface was greater in NT and CP compared to conventional tillage systems (CT, CTb and CTr), due to the higher organic matter content, as well as less soil mobilization. Aggregate stability in water, on the other hand, was affected by the low variation in previous gravimetric moisture of aggregates, which contributed to a high coefficient of variation of this attribute. The geometric mean diameter of water-stable aggregates (GMD WS) was highest in the 0.00-0.05 m layer in the NT system, in the layers 0.05-0.10 and 0.12-0.17 m in the CT, and values were intermediate in CP. The stability index (SI) in the surface layers was greater in treatments where crop residues were kept in the field (NT, CP and CT), which is associated with soil organic matter content. No differences were found in the layer 0.27-0.32 m. The effect of nutrient sources on GMD AD and GMD WS was small and did not affect SI.

Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity.

Acid-sensing ion channels (ASICs) are neuronal H(+)-gated cation channels, and the transient receptor potential vanilloid 1 channel (TRPV1) is a multimodal cation channel activated by low pH, noxious heat, capsaicin, and voltage. ASICs and TRPV1 are present in sensory neurons. It has been shown that raising the temperature increases TRPV1 and decreases ASIC H(+)-gated current amplitudes. To understand the underlying mechanisms, we have analyzed ASIC and TRPV1 function in a recombinant expression system and in dorsal root ganglion (DRG) neurons at room and physiological temperature. We show that temperature in the range studied does not affect the pH dependence of ASIC and TRPV1 activation. A temperature increase induces, however, a small alkaline shift of the pH dependence of steady-state inactivation of ASIC1a, ASIC1b, and ASIC2a. The decrease in ASIC peak current amplitudes at higher temperatures is likely in part due to the observed accelerated open channel inactivation kinetics and for some ASIC types to the changed pH dependence of steady-state inactivation. The increase in H(+)-activated TRPV1 current at the higher temperature is at least in part due to a hyperpolarizing shift in its voltage dependence. The contribution of TRPV1 relative to ASICs to H(+)-gated currents in DRG neurons increases with higher temperature and acidity. Still, ASICs remain the principal pH sensors of DRG neurons at 35°C in the pH range ≥6.

Environmental and agricultural benefits of a management system designed for sandy loam soils of the humid tropics

A sustainable management of soils with low natural fertility on family farms in the humid tropics is a great challenge and overcoming it would be an enormous benefit for the environment and the farmers. The objective of this study was to assess the environmental and agronomic benefits of alley cropping, based on the evaluation of C sequestration, soil quality indicators, and corn yields. Combinations of four legumes were used in alley cropping systems in the following treatments: Clitoria fairchildiana + Cajanus cajan; Acacia mangium + Cajanus cajan; Leucaena leucocephala + Cajanus cajan; Clitoria fairchildiana + Leucaena leucocephala; Leucaena leucocephala + Acacia mangium and a control. Corn was used as a cash crop. The C content was determined in the different compartments of soil organic matter, CEC, available P, base saturation, percentage of water saturation, the period of the root hospitality factor below the critical level and corn yield. It was concluded that alley cropping could substitute the slash and burn system in the humid tropics. The main environmental benefit of alley cropping is the maintenance of a dynamic equilibrium between C input and output that could sustain up to 10 Mg ha-1 of C in the litter layer, decreasing atmospheric CO2 levels. Alley cropping is also beneficial from the agricultural point of view, because it increases base saturation and decreases physical resistance to root penetration in the soil layer 0 - 10 cm, which ensures the increase and sustainability of corn yield.

Cost stickiness revisited: Empirical aplication for farms

This article reviews previous research regarding cost stickiness and performs an empirical analysis applied to a sample of farms. It recognizes that modelization of cost stickiness is a particular case of representation of cost variations as a function of output variations. It also discusses methodological issues and analyses cost stickiness for all registered farm costs and opportunity costs of family work. Costs exhibit a considerable level of rigidity. Even for variable costs, a decrease in activity involves a lower decrease in costs than the amounts involved when activity increases. While registered indirect costs slightly decrease when activity decreases, opportunity costs always increase. The study provides empirical evidence that cost stickiness is significantly reduced with better management decision practices.

The effect of plantation silviculture on soil organic matter and particle-size fractions in Amazonia

Eucalyptus grandis and other clonal plantations cover about 3.5 million ha in Brazil. The impacts of intensively-managed short-rotation forestry on soil aggregate structure and Carbon (C) dynamics are largely undocumented in tropical ecosystems. Long-term sustainability of these systems is probably in part linked to maintenance of soil organic matter and good soil structure and aggregation, especially in areas with low-fertility soils. This study investigated soil aggregate dynamics on a clay soil and a sandy soil, each with a Eucalyptus plantation and an adjacent primary forest. Silvicultural management did not reduce total C stocks, and did not change soil bulk density. Aggregates of the managed soils did not decrease in mass as hypothesized, which indicates that soil cultivation in 6 year cycles did not cause large decreases in soil aggregation in either soil texture. Silt, clay, and C of the sandy plantation soil shifted to greater aggregate protection, which may represent a decrease in C availability. The organic matter in the clay plantation soil increased in the fractions considered less protected while this shift from C to structural forms considered more protected was not observed.

Simulations in evolution. II. Relative fitness and the propagation of mutants.

In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous article presented a histogram model [1] consisting in populations of individuals whose number changed under the influence of variation and/or fitness, the total population remaining constant. Individuals are classified into bins, and the content of each bin is calculated generation after generation by an Excel spreadsheet. Here, we apply the histogram model to a stable population with fitness F(1)=1.00 in which one or two fitter mutants emerge. In a first scenario, a single mutant emerged in the population whose fitness was greater than 1.00. The simulations ended when the original population was reduced to a single individual. The histogram model was validated by excellent agreement between its predictions and those of a classical continuous function (Eqn. 1) which predicts the number of generations needed for a favorable mutation to spread throughout a population. But in contrast to Eqn. 1, our histogram model is adaptable to more complex scenarios, as demonstrated here. In the second and third scenarios, the original population was present at time zero together with two mutants which differed from the original population by two higher and distinct fitness values. In the fourth scenario, the large original population was present at time zero together with one fitter mutant. After a number of generations, when the mutant offspring had multiplied, a second mutant was introduced whose fitness was even greater. The histogram model also allows Shannon entropy (SE) to be monitored continuously as the information content of the total population decreases or increases. The results of these simulations illustrate, in a graphically didactic manner, the influence of natural selection, operating through relative fitness, in the emergence and dominance of a fitter mutant.

Changes in running mechanics and spring-mass behaviour induced by a 5-hour hilly running bout.

Abstract The aim of this study was to investigate changes in running mechanics and spring-mass behaviour with fatigue induced by 5-hour hilly running (5HHR). Running mechanics were measured pre- and post-5HHR at 10, 12 and 14 km · h(-1) on an instrumented treadmill in eight ultramarathon runners, and sampled at 1000 Hz for 10 consecutive steps. Contact (t(c) ) and aerial (t(a) ) times were determined from ground reaction force (GRF) signals and used to compute step frequency (f). Maximal GRF, loading rate, downward displacement of the centre of mass (Δz), and leg length change (ΔL) during the support phase were determined and used to compute both vertical (K(vert) ) and leg (K(leg) ) stiffness. A significant decrease in t(c) was observed at 12 and 14 km · h(-1) resulting in an increase of f at all speeds. Duty factor and F(max) significantly decreased at 10 km · h(-1). A significant increase in K(vert) and K(leg) was observed at all running speeds with significant decreases in Δz and ΔL. Despite the shorter duration, the changes in running mechanics appeared to be in the same direction (increased f and K(vert) , decrease in Δz and F(max) ) but of lower amplitude compared with those obtained after an ultra-trail or an ultramarathon.

Is there a connection between the tax administration and the political power?

This paper offers empirical evidence from Spain of a connection between the tax administration and the political power. Firstly, the regional tax administration is not immune to the budgetary situation of regional government, and tends to exert a greater (or lesser) effort in tax collection the greater (or lower) the (expected) public deficit. At the same time, the system of unconditional grants from the central layer of government provokes an ¿income effect¿ which disincentivises the efforts of the tax administration. Secondly, these efforts also decrease when the margin to lose a parliamentary seat in an electoral district is cut, although the importance of this disincentive decreases according to the parliamentary strength of the incumbent

Microbial and enzymatic activity in soil after organic composting

Microbial activity and biochemical properties are important indicators of the impact of organic composting on soil. The objective of this study was to evaluate some indicators of soil microbial and biochemical processes after application of compost (household waste). A Typic Acrustox, sampled at a depth of 10 cm under Cerrado biome vegetation, was evaluated in three treatments: control (soil without organic compost amendment) and soil with two doses of domestic organic compost (10 and 20 g kg-1 soil). The following properties were evaluated: released C (C-CO2): microbial respiration 15 days after incubation; microbial biomass C (MBC); total glucose (TG); metabolic quotient (qCO2); and enzyme activity of β-glucosidase and acid and alkaline phosphatase. The application of household compost, at doses of 10 and 20 g kg-1 Typic Acrustox, resulted in significant gains in microbial activity, organic C and C stock, as evidenced by increased MBC and TG levels. On the other hand, qCO2 decreases indicated greater microbial diversity and more efficient energy use. The addition of compost, particularly the 20 g kg-1 dose, strongly influenced the enzyme β-glucosidase and phosphatase (acid and alkaline). The β-glucosidase activity was significantly increased and acid phosphatase activity increased more than the alkaline. The ratio of β-glucosidase to MBC was greater in the control than in the composted treatments which suggests that there were more enzymes in the control than in the substrate or that the addition of compost induced a great MBC increase.

Effects of Exemestane and Tamoxifen Treatment on Bone Texture Analysis Assessed by TBS in Comparison With Bone Mineral Density Assessed by DXA in Women With Breast Cancer.

We performed an analysis of a substudy of the randomized Tamoxifen Exemestane Adjuvant Multinational trial to determine the effects of exemestane (EXE) and tamoxifen (TAM) adjuvant treatment on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry compared with the trabecular bone score, a novel grey-level texture measurement that correlates with 3-dimensional parameters of bone texture in postmenopausal women with hormone receptor-positive breast cancer for the first time. In total, 36 women were randomized to receive TAM (n = 17) or EXE (n = 19). Patients receiving TAM showed a mean increase of BMD in lumbar spine from baseline of 1.0%, 1.5%, and 1.9% and in trabecular bone score of 2.2%, 3.5%, and 3.3% at 6-, 12-, and 24-mo treatment, respectively. Conversely, patients receiving EXE showed a mean decrease from baseline in lumbar spine BMD of -2.3%, -3.6%, and -5.3% and in trabecular bone score of -0.9%, -1.7%, and -2.3% at 6-, 12-, and 24-mo treatment, respectively. Changes in trabecular bone score from baseline at spine were also significantly different between EXE and TAM: p = 0.05, 0.007, and 0.006 at 6, 12, and 24mo, respectively. TAM induced an increase in BMD and bone texture analysis, whereas EXE resulted in decreases. The results were independent from each other.

Nedd4-2 ubiquitin ligase: a contributor to experimental neuropathic pain?

Background: Neuropathic pain is associated with altered expression of voltage-gated sodium channels (VGSCs) leading to peripheral nerve hyperexcitability. Interestingly, in cell expression systems, the ubiquitin ligase Nedd4-2 regulates the cell membrane density of the most abundant peripheral and pain-related VGSC, namely Nav1.7, and decreases its sodium current. Yet nothing is known about the involvement of Nedd4-2 in nociception and chronic pain. Therefore, the goal of this study is (i) to characterize Nedd4-2 and Nav1.7 expression in an experimental model of neuropathic pain (ii) to design by viral vector-mediated gene therapy an approach to depict the implication of Nedd4-2 in chronic pain. Methods: Western Blot and immunohistochemistry experiments detecting Nav1.7 and Nedd4-2 were performed in rodent DRGs 7 days after spared nerve injury (SNI). For the viral vector-mediated gene therapy, a recombinant Adeno-Associated Virus (rAAV2/6) was generated expressing the Nedd4-2 gene. Intrathecal injection of rAAV2/6 was followed 2 weeks after by the SNI surgery. Data are expressed in mean ± SEM, n = 4 in each condition. Results: Immunofluorescence on DRGs neurons reveals a decreased number of positive Nedd4-2 cells in the SNI model (27.0 ± 1.2%) versus sham group (43.4 ± 3.5%; p <0.005), as well as an increase in positive Nav1.7 cells in SNI (50.1 ± 2.9%) versus Sham (41.6 ± 1.8%; p <0.05). The change of Nedd4-2 expression was confirmed by western-blot analysis. In addition, we show that Nedd4-2 and Nav1.7 are largely expressed in overlapping cell populations, chiefly colocalizing with markers of small nociceptive neurons. Furthermore, we report that intrathecal injection of rAAV is able to counteract the reduction of Nedd4-2 expression in SNI animals. Conclusion: Our results indicate that Nedd4-2 is mainly expressed in nociceptors and downregulated after nerve injury. Moreover, our data suggest that the reduction of Nedd4-2, after nerve injury, may modulate Nav1.7 activity and contribute to hyperexcitability in neuropathic pain. A normal level of Nedd4-2 can be restored using a viral vector and we will further assess its functional effect on pain sensitivity.