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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.

Background Although extensively studied, the effect of antipsychotics is not completely understood at a network level. We tested the hypothesis that acute administration of haloperidol would modulate functional connectivity of brain regions relevant to schizophrenia pathophysiology. To assess putative changes in brain network properties and regional interactivity, we studied the expression of Homer1a, an Immediate Early Gene (IEG) demonstrated to be induced by antipsychotic administration and coding for a protein involved in glutamatergic synapses remodeling. Methods Sprague-Dawley rats (n = 26) assigned to vehicle (VEH; NaCl 0.9%) or haloperidol (HAL; 0.8 mg/kg) were included in the network analysis. Homer1a mRNA induction was evaluated by in situ hybridization. Signal intensity analysis was performed in 33 Regions of Interest (ROIs) in the cortex, the caudate putamen, and the nucleus accumbens. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs in the two groups. Two networks were generated for HAL and VEH groups, and their properties and topography were explored. Results VEH and HAL networks showed qualitative differences in global efficiency and clustering coefficient. The HAL network showed enhanced interactivity between cortical and striatal regions, and within caudate putamen subdivisions. On the other hand, it exhibited reduced inter-correlations between cingulate cortex and anterior insula and caudate putamen and nucleus accumbens. Moreover, haloperidol was able to modulate centrality of crucial functional hubs. These preclinical results corroborate and expand the clinical evidence that antipsychotics may modulate specific brain network properties and disease-related circuits’ interactivity.

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality".

Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects.

The factors controlling otoconia growth are not well known but it seems that the type of proteins contained in the otoconia regulates the initiation and/or the subsequent rates of crystal growth determining the morphology and the size of the final crystal. In order to clarify the mechanism of otoconia formation and their turnover, major proteins contained in the otoconia from the maculae of the saccule, utricle and lagena of inner ear of lizard Podarcis sicula were analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). Coomassie staining of SDS–PAGE resulted in a major broad band of 15 kDa and four other bands of 21, 28, 45 and 97 kDa. The proteins of 15, 21, 28 and 45 kDa were separated by high-pressure liquid chromatography on a C-4-reverse-phase column and the incubation of blots with monoclonal anti-Calbindin D28K antibodies indicated that the band of 28 kDa was Calbindin D28K, a calcium-binding protein.