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Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG. The level of the endocannabinoid 2-arachidonoylglycerol (2-AG) was instead increased in the LEC. Chronic treatment with PEA, starting from when neuropathic pain was fully developed, was able to reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP in SNI wild type, but not in PPAR? null, mice. PEA also restored the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis. Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.

On 24 August 2016, at 01:36 UTC¸ the intra-Apennine extensional fault system of Central Italy released a destructive earthquake (MW 6.0). It produced widespread damage and fatalities, killing about 300 people and severely destroying the town of Amatrice and surrounding villages. After few hours, the Amatrice earthquake was followed by a significant aftershock (MW 5.5), which nucleated 15 km NW-ward. The epicentral area of the seismic sequence extends in the NNW-SSE direction, for a length of about 25-30 km. It is located at the hanging-wall of the WSW-dipping Vettore-Gorzano active extensional fault system. During the days following the main shock, a significant number of Synthetic Aperture Radar (SAR) data have been acquired from different passes and angles by the L-band ALOS-2, C-band Sentinel-1 and X-band COSMO-SkyMed satellites. This allowed us to map in a very short time the co-seismic ground displacements through the Differential SAR Interferometry (DInSAR) technique, and also to evaluate their Vertical and East-West components with high details. The generated interferometric pattern is characterized by a double-eyed co-seismic shape that spans 20 km along the NNW-SSE direction and that well coincides with the epicentral areas. We modeled the seismic source that well fit the Mw 6.2 event. In particular, for this analysis, we separately applied an analytical Okada approach as well as a 3D Finite Element (FE) numerical modeling, the latter jointly exploiting DInSAR measurements and structural-geological data. The model obtained via the FE approach suggests that the Amatrice 2016 earthquake nucleated at 8 km deep along the intersection line between the Vettoretto-Redentore and the Northern Gorzano faults, and instantly geminated in two rupture patches that radiated with an approximate bilateral symmetry on the two fault planes. The two rupture patches covered differently shaped slip area, with aspect ratio that well recalls the shape of the interferometric lobes of ground subsidence at the two faults hanging wall. The different shapes of the two lobes are partially associated to the different dip-angle of the Vettoreto-Redentore and Gorzano faults (50° ad 60° respectively). In summary, we found evidences of bilateral rupture propagating along two en-echelon faults connected at the hypocenter.

The current study has investigated the involvement of periaqueductal gray (PAG) metabotropic glutamate subtype 7 and 8 receptors (mGluR7 and mGluR8) in modulating rostral ventromedial medulla (RVM) ongoing and tail flick–related ON and OFF cell activities. Our study has also investigated the role of PAG mGluR7 on thermoceptive threshold and PAG glutamate and GABA release. Intra-ventrolateral PAG (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG (2 and 4 nmol/rat)] or N,NI-dibenzhydrylethane-1,2-diamin dihydrochloride (AMN082, (1 and 2 nmol/rat), selective mGluR8 and mGluR7 agonists, respectively, caused opposite effects on the ongoing RVM ON and OFF cell activities. Tail flick latency was increased or decreased by (S)-3,4-DCPG or AMN082 (2 nmol/rat), respectively. (S)-3,4-DCPG reduced the pause and delayed the onset of the OFF cell pause. Conversely, AMN082 increased the pause and shortened the onset of OFF cell pause. (S)-3,4-DCPG or AMN082 did not change the tail flick-induced onset of ON-cell peak firing. The tail flick latency and its related electrophysiological effects induced by (S)-3,4-DCPG or AMN082 were prevented by (RS)--methylserine-o-phosphate (100 nmol/rat), a group III mGluR antagonist. Intra-ventrolateral PAG perfusion with AMN082 (10 and 25 µM), decreased thermoceptive thresholds and glutamate extracellular levels. A decrease in GABA release was also observed. These results show that stimulation of PAG mGluR8 or mGluR7 could either relieve or worsen pain perception. The opposite effects on pain behavior correlate with the opposite roles played by mGluR7 and mGluR8 on glutamate and GABA release and the ongoing and tail flick-related activities of the RVM ON and OFF cells.