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We present the implementation of a global archive of Differential Synthetic Aperture Radar Interferometry (DInSAR) co-seismic deformation maps. The archive has been generated by automatically processing all the Copernicus Sentinel-1 data spanning about 300 significant (at least Mw > 5.5) earthquakes all over the Earth. An empirical relation between magnitude and epicenter depth was considered to limit the study to those earthquakes that can likely induce ground deformation. DInSAR processing has been carried out within a Cloud-Computing (CC) environment, specifically the Amazon Web Services, to benefit of high processing capacity. The generated DInSAR results are then made freely and openly available to the Solid Earth scientific community through the European Planet Observing System (EPOS) Research Infrastructure.

We investigate a large geodetic data set of interferometric synthetic aperture radar (InSAR) and GPS measurements to determine the source parameters for the three main shocks of the 2016 Central Italy earthquake sequence on 24 August and 26 and 30 October (Mw 6.1, 5.9, and 6.5, respectively). Our preferred model is consistent with the activation of four main coseismic asperities belonging to the SW dipping normal fault system associated with the Mount Gorzano-Mount Vettore-Mount Bove alignment. Additional slip, equivalent to a Mw ~ 6.1–6.2 earthquake, on a secondary (1) NE dipping antithetic fault and/or (2) on a WNW dipping low-angle fault in the hanging wall of the main system is required to better reproduce the complex deformation pattern associated with the greatest seismic event (the Mw 6.5 earthquake). The recognition of ancillary faults involved in the sequence suggests a complex interaction in the activated crustal volume between the main normal faults and the secondary structures and a partitioning of strain release.

We present an unsupervised and automatic system for volcano deformation monitoring via the Copernicus Sentinel-1 data. The system relies on the Parallel Small BAseline Subset (P-SBAS) approach, permitting us to generate updated displacement time series at every new Sentinel-1 acquisition over a selected area of interest in a fast and accurate way. The service is currently operative to monitor the main active Italian volcanoes in the framework of cooperation with the Italian Department of Civil Protection. The system is potentially extendable to every area on the Earth, thus making it suitable for surface displacement monitoring of a large variety of phenomena. Finally, the obtained results are made available to the scientific community through the EPOS Research Infrastructure.

We investigate the deformation of Mt. Etna volcano (Italy) by exploiting the DInSAR technique referred to as the Small BAseline Subset (SBAS) algorithm. In particular, we take advantage of the multi-sensor data processing capability of the SBAS algorithm which allows us to generate Mt. Etna mean deformation velocity maps and the corresponding time series in the last twenty-five years. To achieve this task, we exploit different set of SAR data collected by ERS-1/2, ENVISAT, COSMO-SkyMed and Sentinel-1 radar sensors in the 1992-2018 time interval. We, also, show the deformation pattern induced by the recent seismo-volcanic crisis occurring from 24 to 27 December 2018. The main results show that the East-West displacement map highlights the most significant entities, whose maximum values exceed 30 cm towards the West and 40 towards the East on the summit of the volcano. In this scenario, the measurements permit to model the geometry and characteristics of the causative deformation sources; preliminary results suggest the presence of two different sources: a shallow dyke feeding the eruptive activity at summit craters and a major strike-slip fault/s on the southeastern flank nucleating the 26 th mainshock.

We investigate the 24-27 December 2018 eruption of Mount Etna occurred from fissures located on the volcano eastern flank and accompanied by a seismic swarm, which was triggered by the magma intrusion and continued for weeks after the end of the eruption. Moreover, this swarm involved some of the shallow volcano-tectonic structures located on the Mount Etna flanks and culminated on 26 December with the strongest event (M-L 4.8), occurred along the Fiandaca Fault. In this work, we analyze seismological data and Sentinel-1 Differential Interferometric Synthetic Aperture Radar (DInSAR) measurements, the latter inverted through analytical modeling. Our results suggest that a dike source intruded, promoting the opening of the eruptive fissures fed by a shallower dike. Moreover, our findings indicate that the activation of faults in different sectors of the volcano may be considered as a response to accommodate the deformations induced by the magma volumes injection.

We are writing this comment because many aspects of the analysis presented by Nappi et al. (2018) are debatable. In particular, a major issue is relevant to the conclusion suggested by Nappi el al. (2018) about a seismogenic normal fault with northward dip. This finding is not well-founded because the authors do not really present a causative source model. In addition, their statement is clearly not consistent with the Differential Interferometric Synthetic Aperture Radar (DInSAR), Global Positioning System (GPS) and seismological measurements presented in the article previously published by De Novellis et al. (2018). Moreover, we also report an evident error in the geologic map proposed by Nappi et al. (2018, their fig. 3).

We present an unsupervised tool for the automatic generation of co-seismic displacement maps by using satellite Differential Synthetic Aperture Radar Interferometry (DInSAR) technique. The tool relies on the use of Sentinel-1 SLC Interferometric Wide Swath (IWS) data and main earthquake information, the latter retrieved from on-line global catalogs. In particular, the tool collects location, depth and magnitude of a seismic event and immediately triggers the data download and the interferometric process over the area affected by the earthquake. The generated DInSAR results (mainly interferograms and displacement maps) are then made available to the Solid Earth scientific community through the EPOS Research Infrastructure. Moreover, the implemented system is also used to serve the Italian Department of Civil Protection in case of main seismic events in Italy. Finally, due to the Sentinel-1 characteristics, the obtained results can contribute to the generation of a global database of DInSAR co-seismic displacement maps.

The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-induced experimental dysbiosis. Inflammation of the small intestine was also assessed. Mice were exposed to a mixture of antimicrobials for 2 weeks. Afterwards, they received Lactobacillus casei DG (LCDG) or a vehicle for up to 7 days via oral gavage. Perturbation of microbiota was accompanied by a general inflammatory state and alteration of some endocannabinoidome members in the gut. Behavioural changes, including increased immobility in the tail suspension test and reduced social recognition were observed, and were associated with altered BDNF/TrkB signalling, TRPV1 phosphorylation and neuronal firing in the hippocampus. Moreover, morphological rearrangements of non-neuronal cells in brain areas controlling emotional behaviour were detected. Subsequent probiotic administration, compared with vehicle, counteracted most of these gut inflammatory, behavioural, biochemical and functional alterations. Interestingly, levels of Lachnospiraceae were found to significantly correlate with the behavioural changes observed in dysbiotic mice. Our findings clarify some of the biomolecular and functional modifications leading to the development of affective disorders associated with gut microbiota alterations.

We analyze the crustal rheology beneath the active resurgent Campi Flegrei caldera (CFc) in Southern Italy by modelling the 3D brittle-ductile (B/D) transition, based on available thermal, geological and geophysical data. Firstly, the thermal field in the conductive physical regime is modeled using a finite element method; based on an optimization tool, this method is applied to evaluate the location and dimensions of the deep thermal source beneath the caldera. A horizontally-extended thermal anomaly located at about 5000 m depth below sea level is identified beneath Pozzuoli Bay, a part of the CFc. The same isotherm is located at a depth of 20,000 m beyond the caldera. This indicates a higher horizontal temperature gradient in the caldera with respect to the surrounding area. Next, we utilize this thermal model to image the 3D rheological stratification of the shallow crust below the caldera with two different values of strain rates. Within the caldera, the B/D transitions with 3equal to 1012 s 1 and 108 s 1 are located at 3000 m and 5000 m depths, respectively. Outside the caldera, the transition is very deep (15,000e20,000 m), seemingly uninfluenced by the thermal state of the CFc volcanism. Finally, we compare these results with the spatial distribution of earthquake hypocenters, Benioff strain release and b-value distribution to investigate the relationship between crustal rheology and seismicity characteristics. Our analysis reveals that the image of the B/D transition is in agreement with the distribution of earthquake hypocenters, constraining the potential seismogenic volume of the region. Our study demonstrates that knowledge of the rheological state of a volcanic system is an important element to interpret its dynamic, forecast future activity and improve evaluation of the associated seismic hazard. 2018, China University of Geosciences (Beijing) and Peking University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

The causative source of the first damaging earthquake instrumentally recorded in the Island of Ischia, occurred on 21 August 2017, has been studied through a multiparametric geophysical approach. In order to investigate the source geometry and kinematics we exploit seismological, Global Positioning System, and Sentinel-1 and COSMO-SkyMed differential interferometric synthetic aperture radar coseismic measurements. Our results indicate that the retrieved solutions from the geodetic data modeling and the seismological data are plausible; in particular, the best fit solution consists of an E-W striking, south dipping normal fault, with its center located at a depth of 800 m. Moreover, the retrieved causative fault is consistent with the rheological stratification of the crust in this zone. This study allows us to improve the knowledge of the volcano-tectonic processes occurring on the Island, which is crucial for a better assessment of the seismic risk in the area.

The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2X4,7 and P2Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca2+ influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone. GLIA 2014;62:122–132

On 24 August 2016 (01:36 UTC) the intra-Apennine extensional fault system of Central Italy released a ML 6.0 destructiveearthquakebetweenthetownsofNorciaandAmatrice.Themainshockproducedwidespreaddamages and fatalities, devastating several localities and killing about 300 people. The main event was followed by a significant aftershock (ML 5.4), located 15 km to the NW. After one week, the epicentral area reached a length of about 30 km, in the NNW-SSE direction, largely developing at the hanging-wall of the WSW-dipping active extensional Vettore and Gorzano faults. The reconstructed 3D fault model consists in two major interconnected faultsegments,VettoreandGorzano,whichareindividualatdepthshallowerthanabout7-8kmandconvergeinto a unified surface at higher depths; the Vettore-Gorzano unified surface has a length of 65 km, dips WSW-ward with an angle of about 45-50o and reaches a depth of 11 km. By inverting the generated interferograms, following a classical Okada analytical approach, the best modelling results account for two sources related to main shock and more energetic aftershock. The time interval between theascendinganddescending(31August2016)doesnotdiscriminatetheeffectsderivedfromthemain24August event and by its aftershock, but the low magnitude of the second event can only very marginally contribute to the overall deformation pattern. Through Finite Element modelling that jointly exploits DInSAR deformation measurements and structuralgeological data, we reconstruct the 3D source of the Accumoli 2016 normal fault earthquake which fit better a moment Mw 6.2. As results of our modelling, we retrieve (i) the active seismogenic structures responsible for the observed ground deformation, (ii) the spatial distribution of the local stress field in term of volumetric stress and strain. The inversion shows that the co-seismic displacement area was partitioned on two distinct en echelon fault planes, which at the main event hypocentral depth (8 km) merge in one single WSW-dipping surface. Slip peaks were higher along the southern half of the Vettore fault, lower along the northern half of Gorzano fault and null in the relay zone between the two faults; field evidence of co-seismic surface rupture are coherent with the reconstructed scenario.

We analysed the 2012-2013 uplift episode at Fernandina Volcano (Galapagos) through the inverse modeling of Differential Synthetic Aperture Radar Interferometry (DInSAR) ground displacement field. The post-processing analysis of COSMO-SkyMed satellite data revealed that the uplift phenomenon can be divided in three distinctive intervals in which the displacement maintains a nearly constant deformation rate. We used both ascending and descending acquisitions to evaluate the vertical and the horizontal E-W components of the displacement field. The vertical displacement is strongly limited in a narrow region around the caldera rim, where the circumferential fissures that border the summit platform are localized and the E-W component of the horizontal displacement affects the external volcano flanks, up to the apron region. Moreover, we exploited the DInSAR time-series by performing a cross-correlation analysis: both vertical and E-W cross-correlated maps confirm that the observed uplift episode is related to the existence of a single active source, approximated as a pipe-like source. Indeed, our results, obtained through an inverse modeling approach by investigating different type of analytic sources, suggest the existence of an over pressurized pipe-like source, with a slight dip toward SE and located beneath the summit caldera region. The modeled geodetic source could represent the shallower part of an extended and deeper magmatic reservoir.

We investigate the co-seismic effects of the Mw 7.8 Gorkha earthquake through a Finite Element modelling approach that jointly exploits space-borne DInSAR deformation measurements and geologic-structural information. Our model permits to retrieve the coseismic displacements with a very good accuracy and to confirm the finding of earlier studies suggesting that the slip reaches a maximum value of about 7 m at a depth of 7–15 km along the Main Himalayan Thrust (MHT) and occurs in an area about 30 km northern of Kathmandu. In particular, the main-shock ruptured the deep part of the seismogenic zone of MHT, with rather small displacement values retrieved along the splay faults (Main Frontal Thrust – MFT; Main Boundary Thrust – MBT) in the southern region. A relevant aspect of our results is the imaging of about 3 m of displacement in correspondence to the shallow portion of the Main Central Thrust (MCT) to the north and of the Munsiari/Mahabharat Thrust (MT) to the south; this finding may be associated to a possible mechanism for accommodating the MHT-sourced deformation on the adjacent thrusts, highlighting a passive role of the hinterland structures as receiver faults of the displacements transferred from earthquakes originating on the MHT. In addition, the proposed model allow us to map the stress field distribution (evaluated through von Mises failure criteria) associated to the main seismic event; this result is in good agreement with the hypocentral distribution and mechanism of the investigated aftershocks.

In this paper we develop a model of the ground deformation behaviour occurred at Ischia Island (Southern Italy) in the 1992–2010 time period. The model is employed to investigate the forces and physical parameters of the crust controlling the subsidence of the Island. To this aim, we integrate and homogenize in a Finite Element (FE) environment a large amount of data derived from several and different observation techniques (i.e., geological, geophysical and remote sensing). In detail, the main steps of the multiphysics model are: (i) the generation of a 3D geological model of the crust beneath the Island by merging the available geological and geophysical information; (ii) the optimization of a 3D thermal model by exploiting the thermal measurements available in literature; (iii) the definition of the 3D Brittle/Ductile transition by using the temperature distribution of the crust and the physical information of the rocks; (iv) the optimization of the ground deformation velocity model (that takes into account the rheological stratification) by considering the spatial and temporal information detected via satellite multi-orbit C-Band SAR (Synthetic Aperture Radar) measurements acquired during the 1992–2010 time period. The achieved results allow investigating the physical process responsible for the observed ground deformation pattern. In particular, they reveal how the rheology modulates the spatial and temporal evolution of the long-term subsidence phenomenon, highlighting a coupling effect of the viscosities of the rocks and the gravitational loading of the volcano edifice. Moreover, the achieved results provide a very detailed and realistic velocity field image of the subsurface crust of the Ischia Island Volcano.

BACKGROUND AND PURPOSE The amphibian peptide Bv8 induces potent nociceptive sensitization in rodents. Its mammalian homologue, prokineticin 2 (PROK2), is strongly up-regulated in inflamed tissues and is a major determinant in triggering inflammatory pain. Bv8 and PROK2 activate two closely related GPCRs, PK1 and PK2, in a relatively non-selective fashion. To characterize better the roles of the two receptors in hyperalgesia and to obtain ligands whose binding affinity and efficacy differed for the two receptors, we modified the Bv8 molecule in regions essential for receptor recognition and activation. EXPERIMENTAL APPROACH We modified the Bv8 molecule by substituting Trp in position 24 with Ala (A-24) and compared it with Bv8 for binding and activating PK1 and PK2 receptors in cell preparations and in affecting nociceptive thresholds in rodents. KEY RESULTS A-24 preferentially bound to PK2 receptors and activated them with a lower potency (5-fold) than Bv8. When systemically injected, A-24 induced Bv8-like hyperalgesia in rats and in mice, at doses 100 times higher than Bv8. Locally and systemically injected at inactive doses, A-24 antagonized Bv8-induced hyperalgesia. In rat and mouse models of inflammatory and post-surgical pain, A-24 showed potent and long-lasting anti-hyperalgesic activity. Unlike Bv8, A-24 increased β-endorphin levels in mouse brain. CONCLUSIONS AND IMPLICATIONS A-24 induced its anti-hyperalgesic effect in rodents by directly blocking nociceptor PK1 receptors and by activating the central opioid system and the descending pain control pathway through brain PK2 receptors.

L'identificazione, l'analisi ed il monitoraggio delle deformazioni della superficie terrestre e la successiva modellazione geofisica delle sorgenti di deformazione forniscono informazioni fondamentali per la valutazione e gestione di scenari di rischio e per la corretta pianificazione delle attività umane e del territorio. In questo contesto si colloca l'Accordo Operativo che l'Istituto per il Rilevamento Elettromagnetico dell'Ambiente (IREA) del Consiglio Nazionale delle Ricerche (CNR) ha stipulato con il Ministero dello Sviluppo Economico (MiSE). Tale Accordo ha lo scopo di effettuare un monitoraggio delle deformazioni superficiali delle aree di interesse per il MiSE, con particolare riferimento ai siti pilota sui quali saranno sperimentate per la prima volta gli Indirizzi e Linee Guida per il monitoraggio delle attività di sottosuolo, mediante analisi interferometriche e modellazioni multi-parametriche e multi-fisiche. Le prime consentono di ottenere informazioni sulla distribuzione spaziale delle deformazioni superficiali e sulla loro evoluzione temporale, le seconde sui processi geofisici/geologici che caratterizzano le aree investigate. In questo lavoro sono mostrati i risultati preliminari prodotti nell'ambito del suddetto Accordo. In particolare, sono presentati e discussi i risultati ottenuti mediante analisi interferometriche effettuate utilizzando dati SAR acquisiti dal sensore Sentinel-1A sulla porzione dell'Italia meridionale che va dal Golfo di Napoli al Golfo di Taranto. Inoltre, è presentata una modellazione geologica 3D dell'area epicentrale degli eventi sismici che hanno interessato l'Emilia nel maggio 2012; la modellazione, seppur preliminare, costituisce la base sulla quale verrà sviluppato una modellazione multi-fisica avanzata delle sorgenti di deformazione nell'area considerata.

Background and purpose: N-arachidonoyl-serotonin (AA-5-HT) is an inhibitor of fatty acid amide hydrolase (FAAH)-catalysed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA). We investigated if AA-5-HT antagonizes the transient receptor potential vanilloid-1 (TRPV1) channel and, as FAAH and TRPV1 are targets for analgesic compounds, if it exerts analgesia in rodent models of hyperalgesia. Experimental approach: AA-5-HT was tested in vitro, on HEK-293 cells overexpressing the human or the rat recombinant TRPV1 receptor, and in vivo, in rats and mice treated with formalin and in rats with chronic constriction injury of the sciatic nerve. The levels of the endocannabinoids, AEA and 2-arachidonoylglycerol, in supraspinal (periaqueductal grey, rostral ventromedial medulla), spinal or peripheral (skin) tissues were measured. Key results: AA-5-HT behaved as an antagonist at both rat and human TRPV1 receptors (IC50=37-40 nM against 100 nM capsaicin). It exerted strong analgesic activity in all pain models used here. This activity was partly due to FAAH inhibition, elevation of AEA tissue levels and indirect activation of cannabinoid CB1 receptors, as it was reversed by AM251, a CB1 antagonist. AA-5-HT also appeared to act either via activation/desensitization of TRPV1, following elevation of AEA, or as a direct TRPV1 antagonist, as suggested by the fact that its effects were either reversed by capsazepine and 5′-iodo-resiniferatoxin, two TRPV1 antagonists, or mimicked by these compounds administered alone. Conclusions and implications: Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA-5-HT was highly effective against both acute and chronic peripheral pain. British Journal of Pharmacology (2007) 150, 766–781. doi:10.1038/sj.bjp.0707145

In this study, the effect of ( S )-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of ( S )-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic ( S )-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when ( S )-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG ( RS )-α-methylserine- O -phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of ( S )-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG ( S )-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. ( S )-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Background Enhanced supraspinal glutamate levels following nerve injury are associated with pathophysiological mechanisms responsible for neuropathic pain. Chronic pain can interfere with specific brain areas involved in glutamate-dependent neuropsychological processes, such as cognition, memory, and decision-making. The medial prefrontal cortex (mPFC) is thought to play a critical role in pain-related depression and anxiety, which are frequent co-morbidities of chronic pain. Using an animal model of spared nerve injury (SNI) of the sciatic nerve, we assess bio-molecular modifications in glutamatergic synapses in the mPFC that underlie neuropathic pain-induced plastic changes at 30 days post-surgery. Moreover, we examine the effects of palmitoylethanolamide (PEA) administration on pain-related behaviours, as well as the cortical biochemical and morphological changes that occur in SNI animals. Results At 1 month, SNI was associated with mechanical and thermal hypersensitivity, as well as depression-like behaviour, cognitive impairments, and obsessive-compulsive activities. Moreover, we observed an overall glutamate synapse modification in the mPFC, characterized by changes in synaptic density proteins and amino acid levels. Finally, with regard to the resolution of pain and depressive-like syndrome in SNI mice, PEA restored the glutamatergic synapse proteins and changes in amino acid release. Conclusions Given the potential role of the mPFC in pain mechanisms, our findings may provide novel insights into neuropathic pain forebrain processes and indicate PEA as a new pharmacological tool to treat neuropathic pain and the related negative affective states. Graphical Abstract Palmitoylethanolamide: a new pharmacological tool to treat neuropathic pain and the related negative affective states. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0139-5) contains supplementary material, which is available to authorized users.

In this work we propose a numerical optimization procedure constrained by field and SBAS-DInSAR measurements, as an alternative to standard forward Finite Elements (FE) models, to deeply analyze slope instabilities. The performed optimization procedure is based on the minimization of the difference between SBAS-DInSAR data and the results of the FE model, in terms of the displacement rate. As case study to evaluate the performances of the proposed procedure, we select the Ivancich landslide, located in the eastern part of the Assisi municipality (central Italy), and affected by an active slow-moving landslide since its first urbanization process. In this case, we focused on the Newtonian approach by considering a creeping flow approximation, suitable to simulate the kinematic trend of the investigated site. In addition, a set of 39 SAR images, acquired by COSMO-SkyMed constellation between 2009 and 2012, was exploited to generate deformation time series.

Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 cannabinoid receptors. We assessed here their functional activity. Experimental approach: The effect of the two compounds on forskolin-induced cAMP formation in intact cells or GTP-γ-S binding to cell membranes, and their action on nociception in vivo was determined. Key results: CB-25 enhanced forskolin-induced cAMP formation in N18TG2 cells (EC50∼20 nM, max. stimulation=48%), behaving as an inverse CB1 agonist, but it stimulated GTP-γ-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50=100 nM, max. stimulation=48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB1-CHO cells (EC50=1600 nM, max. inhibition=68% of CP-55,940 effect). CB-52 inhibited forskolin-induced cAMP formation by N18TG2 cells (IC50=450 nM, max. inhibition=40%) and hCB1-CHO cells (EC50=2600 nM, max. inhibition=62% of CP-55,940 effect), and stimulated GTP-γ-S binding to mouse brain membranes (EC50=11 nM, max. stimulation∼16%). Both CB-25 and CB-52 showed no activity in all assays of CB2-coupled functional activity and antagonized CP55940-induced stimulation of GTP-γ-S binding to hCB2-CHO cell membranes. In vivo, both compounds, administered i.p., produced dose-dependent nociception in the plantar test carried out in healthy rats, and antagonised the anti-nociceptive effect of i.p. WIN55,212-2. In the formalin test in mice, however, the compounds counteracted both phases of formalin-induced nociception. Conclusions and implications: CB-25 and CB-52 behave in vitro mostly as CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors. British Journal of Pharmacology (2006) 149, 431–440. doi:10.1038/sj.bjp.0706888

Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. It is a devastating and difficult to manage consequence of peripheral nerve injury and has a variety of clinical symptoms. Neuropathic pain is a major health problem. It has been estimated that 70% of patients with advanced cancer and inflammatory pathologies are afflicted by chronic pain. About 95% of patients with spinal cord injuries have neuropathic pain problems. Chronic pain is debilitating and cause of depression and decreasing quality of life. Pharmacological treatment for the symptoms of painful neuropathy is difficult, because there has been limited understanding of the underlying causes and systemic levels that an effective dose can have on multiple side effects. The use of molecular methods, such as gene therapy, stem cell therapy and viral vector for delivery of biologic antinociceptive molecules, has led to a better understanding of the underlying mechanisms of the induction of intractable neuropathic pain.

This study was undertaken to analyze the involvement of periaqueductal gray (PAG) cannabinoid or group I metabotropic glutamate receptors in the formalin-induced changes on the rostral ventromedial medulla (RVM) ON- and OFF-cells activities. S.c. injection of formalin into the hind paw produced a transient decrease (4–6 min) followed by a longer increase (25–35 min) in tail flick latencies. Formalin also increased basal activity in RVM ON-cells (42+/- 7%) and decreased it in OFF-cells (35+/-4%). Intra-PAG microinjection of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[ 1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212–2) (2 nmol/rat), a cannabinoid receptor agonist, prevented the formalin-induced changes in RVM cell activities. Higher dosages of WIN 55,212–2 (4–8 nmol/rat) increased the tail flick latencies, delayed the tail flick-related onset to ON-cell burst, and decreased the duration of OFFcell pause. Furthermore, WIN 55,212–2 at a dosage of 8 nmol/ rat decreased RVM ON-cell (57+/-7%) and increased OFF-cell ongoing activities (26+/-4%). These effects were prevented by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl- 3-pyrazolecarboxamide SR141716A, (1 pmol/rat), a CB1 cannabinoid receptor antagonist, or by 2-methyl-6-(phenylethynyl) pyridine (MPEP 20 nmol/rat), a selective mGlu5 glutamate receptor antagonist. T7-(hydroxyimino) cyclopropa[b]chromen- 1*-carboxylate ethyl ester (CPCOOE/50 nmol/rat) and (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385, 20 nmol/rat), selective mGlu1 glutamate receptor antagonists, were ineffective in preventing the WIN-induced effects. This study suggests that s.c. injection of formalin modifies RVM neuronal activities and this effect is prevented by PAG cannabinoid receptor stimulation. Moreover, the physiological stimulation of PAG mGlu5, but not mGlu1 glutamate receptors, seems to be required for the cannabinoid-mediated effect.

Iba-1 immunoreactivity (Iba-1-ir) is shown in the m-PFC of sham or SNI mice (30 days after injury) following PEA (10 mg/kg, i.p.) or vehicle treatment (A). Quantitative analysis of total, or activated or hyperbranched, is shown in “B”. Data are expressed as mean ± S.E.M of 3 mice per group. * indicates significant differences compared to sham/vehicle. P

The aim of this study was to investigate whether nitric oxide (NO) is involved in cardiorespiratory regulation in the nucleus tractus solitarii (NTS). Unilateral microinjections (50 nl) of the NO-donor, sodium nitroprusside (SNP, 40-100-200 mM), into the NTS of anaesthetized rats elicited dose-dependent apnea (7.3 +/- 2.3 sec; 28.6 +/- 5.7 sec; 35.6 +/- 6.4 sec, respectively; n = 6) and a decrease in arterial blood pressure (8.4 +/- 3.1 mmHg; 18.2 +/- 5.8 mmHg; 25.8 +/- 6.7 mmHg, respectively; n = 6). Similarly, unilateral micro-injections (50 nl) of another NO-donor, 3-morpholinosydnonimine (SIN-1, 20-40-100 mM), also induced apnea (5.1 +/- 2.4 sec; 8.7 +/- 4.3 sec; 26.3 +/- 6.4 sec, respectively; n = 6) and a decrease in arterial blood pressure (6.2 +/- 2.3 mmHg; 11.1 +/- 3.3 mmHg; 18.3 +/- 6.1 mmHg, respectively; n = 6). The SNP- and SIN-1-induced apnea and arterial blood pressure decrease were significantly (p < 0.01) blocked by a 3 min pretreatment with two calcium-channel blockers, diltiazem (0.1 mM) and cobalt (10 mM), while lower doses (diltiazem 0.01 and cobalt 1) were ineffective. Microinjections of diltiazem (0.01 mM) and cobalt (1 mM) alone did not induce any change in basal cardiorespiratory values like diltiazem (0.1 mM) and cobalt (10 mM). These data suggest that NO may be involved in NTS cardiorespiratory regulation via calcium-channel activation.

Arterial hypertension induced by microinjections of N-methyl-D-aspartate (NMDA) (2 nmol/rat) into the midbrain periaqueductal gray matter was used to assess the involvement of opioid receptors (mu, delta and kappa) in modulating pressor periaqueductal gray neurons. Groups (n = 5-8) of urethane-anaesthetised rats received, 5 min before NMDA, microinjections of selective opioid receptor antagonists in the periaqueductal gray area and arterial blood pressure was monitored. Pretreatments with naloxone (5 nmol/rat), a non selective mu receptor antagonist, or naltrindole hydrochloride (5 nmol/rat), a selective delta receptor antagonist, significantly (P < 0.05) decreased by 31% and 37%, respectively, NMDA-induced hypertension. The latency for the maximum increase of NMDA-induced hypertension was also significantly (P < 0.05) increased with naloxone. Pretreatment with nor-binaltorphimine (5 nmol/rat), a selective kappa receptor antagonist, only increased the latency of NMDA-induced hypertension. Each opioid antagonist failed per se to alter arterial blood pressure. Microinjection of morphine (13 nmol/rat), a non selective mu receptor agonist, significantly decreased (P < 0.05) by 57.5% NMDA-induced arterial hypertension and this effect was antagonised by naloxone. Combined pretreatments in the periaqueductal gray area with naloxone and the GABAA antagonist bicuculline (2.5 nmol/rat; 5 min before naloxone) antagonised the effect of naloxone on NMDA-induced hypertension. In contrast, bicuculline significantly (P < 0.05) potentiated morphine-induced decrease of NMDA hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

In conscious rabbits the intravenous (IV) injection of vasopressin (1 IU/kg IV) induced a coronarocostrictor effect and an increase in S-T segment and T wave amplitude. These changes were accompanied by sinus bradycardia and cardiac arrythmias. The injection of pyridostigmina (250 μg/kg), a reversible cholinesterase inhibitor with predominant muscarinic effects, failed to antagonize the coronarocostrictor effect of vasopressin, as judged by the changes in electrocardiographic recordings.

Purpose. The aim of this work was to develop nanosystems for the use of zoledronic acid (ZOL) in the treatment of symptoms associated with neuropathic pain and to assess the potential antineuropathic effect and the potential targets in the spinal cord (neurons, astrocytes, microglia). Materials and methods. PEGylated liposomes containing ZOL (lipoZ) were prepared by the reverse phase evaporation technique followed by extrusion, purification and lyophilization. The effectiveness of lipoZ was evaluated in an animals model of peripheral neuropathy, spared nerve injury (SNI). In particular, we evaluated the effects of lipoZ on mechanical allodynia. Finally, morphological assessments at the dorsal horn of the spinal cord (L4-L6) were made to investigate a potential action of lipoZ on reactive gliosis associated with neuropathic pain. Results. LipoZ with mean diameter of about 241 nm and an actual loading of ZOL between about 101 ???g ZOL/mg lipids were prepared. In vivo studies showed a significant reduction of mechanical allodynia after treatment with lipoZ; the treatment with free ZOL and blank liposomes were not produced any effect. The morphological analysis of the spinal cord of neuropathic mice, after treatment with blank liposomes, showed a change in the morphology of the astrocytes, as they are hypertrophied in the dorsal horn; this hypertrophy was not observed in mice treated with lipoZ. In addition, treatment with lipoZ produced an increase of IL-10, an anti-inflammatory cytokine, in astrocytes. Conclusions. For the first time, through the use of nanotechnology, the activity of ZOL for the treatment of neuropathic pain was demonstrated in vivo.

A number of thienocinnolin-3-(2 H )-ones ( 2b, c; 3a, b ) have been synthesized and tested for their pharmacological profile. These were compared with the bioisoster 8-acetylamino-4,4 a ,5,6-tetrahydrobenzo( h )cinnolin-3-(2 H )-one 1 , which we reported to be a potent antihypertensive and antithrombotic agent. Binding studies on phosphodiesterase (PDE) isoenzymes indicate that the test compounds exhibited a modest affinity towards PDE III ( 2c, 3a, b ) and PDE V ( 2b, c ). In vivo tests indicated that only 3b displayed antihypertensive properties comparable to the model while all the new derivatives exhibited lower hypotensive activity. All compounds, with the exception of 2b , were more potent than 1 in inhibiting collagen-induced platelet aggregation. Molecular mechanics calculations were performed on compounds 2 and 3 which were compared with the model 1 .

The synthesis of novel 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles 4a-f, starting from N-phenyl-3,4-dihydro-1(2H)-oxonaphthalene-2-carbothioamide and the proper arylhydrazines, is described. Title compounds were evaluated for antiinflammatory, analgesic, antipyretic, antiarrhythmic, hypotensive, local anaesthetic and platelet antiaggregating activities; some of them showed an appreciable antiarrhythmic activity in rats and a good level of infiltration anaesthesia in mice.

Introduzione. L’acido zoledronico (ZOL) è il più potente inibitore dell’attività degli osteoclasti. Studi pre-clinici hanno dimostrato che ZOL, in modelli animali di dolore da metastasi ossee, riduce significativamente l’allodinia e l’iperalgesia meccanica associata con neuropatia periferica, nonché l’infiammazione. Tuttavia, la breve emivita ed il rapido accumulo di ZOL nel tessuto osseo, impediscono al farmaco di raggiungere concentrazioni farmacologicamente attive in alcuni distretti tissutali. Scopo del lavoro. Sviluppare nanosistemi che consentano l’impiego di ZOL nel trattamento dei sintomi associati al dolore neuropatico e valutarne il potenziale effetto antineuropatico ed i potenziali target a livello spinale (neuroni, astrociti, microglia). Materiali e metodi. Liposomi PEGhilati contenenti ZOL (lipoZ) sono stati preparati mediante la tecnica di evaporazione in fase inversa seguita da estrusione, purificazione e liofilizzazione. L’efficacia dei lipoZ è stata valutata in un modello murino di neuropatia periferica, la spared nerve injury (SNI). In particolare, sono stati valutati gli effetti sull’allodinia meccanica e sono state effettuate valutazioni morfologiche a livello delle corna dorsali del midollo spinale (L4-L6) al fine di investigare una potenziale azione di lipoZ nella gliosi reattiva spinale associata a dolore neuropatico. Risultati. Sono stati preparati lipoZ con dimensioni comprese tra 203 e 241 nm ed un contenuto di ZOL compreso tra circa 77 e 101 g/mg di lipidi. Studi in vivo hanno dimostrato una significativa riduzione di allodinia meccanica in seguito a trattamento con lipoZ; il trattamento con ZOL libero e liposomi bianchi non produce alcun effetto. Dall’analisi morfologica del midollo spinale dei topi neuropatici, in seguito a trattamento con liposomi bianchi, è stato osservato un cambiamento della morfologia degli astrociti, in quanto risultano ipertrofici nelle corna dorsali mentre tale ipertrofia non è stata riscontrata nei topi trattati con lipoZ. Inoltre, il trattamento con lipoZ determina un aumento di IL-10, una citochina antinfiammatoria, negli astrociti. Conclusioni. Grazie all’impiego delle nanotecnologie è stata dimostrata un’attività di ZOL nel trattamento dei sintomi del dolore neuropatico in vivo.

Metabotropic glutamate receptors (mGluRs) are a family of G-protein-coupled receptors which play an important role in the modulation of nociception transmission and plasticity [1,2]. In this review we will consider the control of supraspinal nociception by mGluR ligands in several animal models of pain through behavioural and biochemical approaches. More specifically, we will focus our attention on the mGluRs of the midbrain periaqueductal gray (PAG), which has been recognized as an antinociceptive area since 1969. The multiplicity of responses associated with mGluR stimulation is complicated by the localization of these receptors on a variety of pre- and postsynaptic elements of either glutamate, GABA and non-GABA containing neurons that characterize the PAG circuitry. In particular, excitatory-postsynaptic group I mGlu1/5 subtype receptors produce a preferential activation of descending excitatory antinociceptive pathways at the PAG level, while group III mGlu8 receptors modulate the release of glutamate and GABA conversely. Indeed, selective stimulation of mGlu8 receptors generates an increase in glutamate and a decrease in γ-aminobutyric acid (GABA) extracellular levels. These data, together with the evidence that these receptors are present presynaptically on both symmetrical and asymmetrical synapses, justify that their stimulation relieves hyperalgesia in inflammatory pain. Unlike mGlu8, the mGlu7 receptors in the PAG inhibit antinociception via negative modulation of glutamate release, as they seem expressed mainly on asymmetrical synapses. In this review we aim to illustrate the role of mGluRs in controlling nociceptive processes, as well as their interaction with other neurotransmitters within the PAG, in the hope that further findings in this field will pave the way for the development of useful new agents in pain therapy.

This study was undertaken in order to investigate the effect of 2-chloro-2′- C -methyl-N 6 -cyclopentyladenosine (2′-Me-CCPA), a potent and highly selective adenosine A 1 receptor agonist, on nociceptive responses and on the ongoing or tail flick-related changes of rostral ventromedial medulla (RVM) ON- and OFF-cell activities. Systemic administrations of 2′-Me-CCPA (2.5–5 mg/kg, i.p.) reduced the nociceptive response in the plantar and formalin tests, in a way prevented by DPCPX (3 mg/kg, i.p.), a selective A 1 receptor antagonist. Similarly, intra-periaqueductal grey (PAG) 2′-Me-CCPA (0.5–1–2 nmol/rat) reduced pain behaviour in the plantar and formalin tests, in a way inhibited by DPCPX (0.5 nmol/rat). Moreover, when administered systemically (2.5–5 mg/kg, i.p.) or intra-PAG (0.5–1 nmol/rat) 2′-Me-CCPA increased the tail flick latencies, delayed the tail flick-related onset of the ON-cell burst and decreased the duration of the OFF-cell pause in a dose dependent manner. Furthermore, it decreased RVM ON-cell and increased OFF-cell ongoing activities. The in vivo electrophysiological effects were all prevented by DPCPX (0.5 nmol/rat). This study confirms the role of adenosine A 1 receptors in modulating pain and suggests a critical involvement of these receptors within PAG–RVM descending pathway for the processing of pain.

Metabotropic glutamate (mGlu) and cannabinoid receptors are G-protein coupled receptors which have shown synaptic co-operation through small lipid messengers in the central nervous system (CNS). A functional interaction between these two receptor families could have a relevant potential in the treatment of CNS disorders, including chronic pain. Indeed, both mGlu and cannabinoid receptors play a crucial role in the neurobiology of pain and their simultaneous manipulation could lead to novel strategies in pain management. In particular, as both mGlu and cannabinoid receptors have been found in the periaqueductal gray (PAG), a crucial station in the pain modulatory system, these receptors could be a substrate for producing analgesia at this level. In this review we aim to briefly illustrate the role of mGlu and can-nabinoid receptors in controlling nociceptive processes, some points of convergence, and their functional interaction in pain processing. Further insights into this functional linkage between the mGlu and cannabinoid receptors could pave the way to a new strategy for pain relief, such as a drug cocktail acting on cannabinoid/metabotropic glutamate receptors.

The distribution of pyroclasts from 79 A.D. eruption of Vesuvius is analysed to assess the ejection velocities of ballistic particles pertaining to the white and gray eruption phases. This distribution is related to the energy of the eruptive mixture and conditions of the atmosphere during the eruption. Ballistic debris is common in the deposits, and within the sampled area (3–14 km S-SE from the vent) the ejected blocks are scattered throughout the fine-grained pumice fall. We measured about 300 ballistic blocks with diameters between 0.07 and 1 m. Some fragments as large as 0.3 m are located at 9 km from the vent, which probably represents the ballistic limit of such fragments. By using a ballistic model for large blocks permitted an assessment of their initial velocities which range from 170 to 2300m/s, and since some of these velocities exceed the maximum observed velocities of plinian eruptions we conclude that the ballistic model is deficient. The trajectories of smaller blocks (0.1

L-BOAA (1 microgram/mouse), microinjected into the ventrolateral periaqueductal gray (PAG) matter, induced a strong reaction of forward avoidance (running) for 20-30 s in 18% of the mice and immobility for 7 +/- 2 min in 72% of the mice from a total of 68 treated animals. Effects were also observed for grooming and clonus in 6% and 4% of the mice, respectively. Duration of L-BOAA-induced immobility was significantly (p0.05) reduced by a pretreatment with CNQX (0.5 microgram/mouse), a selective antagonist of AMPA glutamergic subtype receptors, but not by a pretreatment with 2-APV (0.5 microgram/mouse), a selective antagonist of NMDA glutamergic subtype receptors, nor by 2-AP3 (0.5 microgram/mouse), a weak antagonist of metabotropic glutamergic subtype receptors. AMPA (0.05 microgram/mouse), also microinjected into ventrolateral PAG, induced the same pattern of behavioural effects as L-BOAA. Forward avoidance, grooming, and clonus induced by L-BOAA or AMPA were also significantly antagonised by a pretreatment with CNQX (data not shown).

In this study we investigated the effects of type I and II mGlu receptors ligands in glycine extracellular concentrations at the periaqueductal gray (PAG) level by using in vivo microdialysis, in conscious rats. An agonist of type I mGlu receptors, (S)-3,5-DHPG (1 and 5 mM), but not a selective agonist for mGlu5 receptors, CHPG (3 and 5 mM), was noticed to increase the dialysate glycine levels in a concentration-dependent manner (60+/-15% and 136+/-13%, respectively). CPCCOEt (1mM), a selective mGlu1 receptor antagonist, perfused in combination with (S)-3,5-DHPG, counteracted the effect induced by (S)-3,5-DHPG, but did not change per se the extracellular PAG glycine values, even at the highest dosage used (2 mM). MPEP (1 and 2 mM), a selective antagonist of mGlu5 receptor, did not modify extracellular glycine level. An agonist of type II mGlu receptors, 2R,4R-APDC (25 and 50 microM), decreased the dialysate glycine in a concentration-dependent manner (-26+/-4% and -54+/-6%, respectively). The 2R,4R-APDC-induced decrease in extracellular glycine was prevented by EGlu (0.5 mM), a selective type II mGlu receptors antagonist. EGlu (0.5 and 1 mM), per se, led to a significant decrease (-56+/-7% and -57+/-2%, respectively) in extracellular PAG glycine too. This effect was prevented by DPCPX (100 microM), a selective antagonist for A1 adenosine receptors, but was not affected by CPA (1 mM), a selective A1 adenosine receptors agonist. Intra-PAG perfusion of CPA (0.1-1 mM) decreased the extracellular PAG glycine values (-47+/-13%) with 1 mM concentration. The CPA-induced effect was prevented by DPCPX (100 microM), and resulted to be additive with the 2R,4R-APDC-induced decrease in glycine values. DPCPX (1 mM) increased per se extracellular glycine (48+/-7%) at the highest dose used. Dipyridamole (100 microM), an inhibitor of both adenosine reuptake and phosphodiesterases, decreased extracellular glycine (-28+/-7%). Extracellular concentrations of glutamine never changed throughout this study. These data show opposing effects of type I and II mGlu receptors in the regulation of PAG glycine values. Moreover, functional interaction between type II mGlu and adenosine A1 receptors, which possibly operate through a common transductional pathway, may be relevant in the physiological control of glycine release in awake, freely moving rats at the periaqueductal gray matter.

The purpose of this study was to evaluate the possible contribution of metabotropic glutamate receptors (mGluRs) to cannabinoid-induced antinociception in the periaqueductal grey (PAG) matter of rats. Intra-PAG microinjection of WIN 55,212-2, a cannabinoid receptor agonist, increased the latency of the nociceptive reaction (NR) in a dose-dependent fashion in the plantar test. This effect was prevented by pretreatment with SR141716A, a selective antagonist of CB1 receptors. When injected alone, SR141716A produced, with the highest dosage used, a significant reduction in the latency of the NR. CPCCOEt, a selective mGlu1 receptor antagonist, was unable to prevent the analgesia produced by WIN 55,212-2. On the contrary, MPEP, a selective mGlu5 receptor antagonist, completely antagonized the effect of WIN 55,212-2. However, the analgesia induced by CHPG, a selective mGlu5 receptor agonist, was blocked by MPEP but not by SR141716A. When injected alone, CPCOOEt produced no effect, whereas MPEP produced, with the highest dosage used, a significant reduction in the latency of the NR. These data emphasize that mGlu5 receptors, but not mGluR1, may modulate nociception in the PAG. Similarly, a pretreatment with either 2-(S)-alpha-EGlu or (RS)-alpha-MSOP, selective antagonists for group II and III mGluRs, respectively, prevented the WIN 55,212-2-induced analgesia. When the higher dosage of (RS)-alpha-MSOP was used a decrease in the latency of the NR was observed. This was not the case for 2-(S)-alpha-EGlu. Pretreatment with DL-AP5, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors, blocked the effect of WIN 55,212-2, and by increasing the dosage strongly reduced per se the latency of the NR. This study suggests that endogenous glutamate could tonically modulate nociception through mGlu and NMDA receptors in the PAG matter. In particular, the physiological stimulation of these receptors seems to be required for the cannabinoid-induced analgesia in this midbrain area.