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Giovanni VITALE

Ricercatore Universitario
Dipartimento di Scienze della Vita sede ex-Scienze Biomediche

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Pubblicazioni

2023 - Adherence to Mediterranean diet in liver transplant recipients: a cross-sectional multicenter study [Articolo su rivista]
Gitto, Stefano; Golfieri, Lucia; Sofi, Francesco; Tamè, Maria R; Vitale, Giovanni; DE Maria, Nicola; Marzi, Luca; Mega, Andrea; Valente, Giovanna; Borghi, Alberto; Forte, Paolo; Cescon, Matteo; DI Benedetto, Fabrizio; Andreone, Pietro; Petranelli, Marco; Dinu, Monica; Carrai, Paola; Arcangeli, Giulio; Grandi, Silvana; Lau, Chloe; Morelli, Maria Cristina; DE Simone, Paolo; Chiesi, Francesca; Marra, Fabio
abstract

Background: Seeing the importance of healthy diet after liver transplant (LT), our study aimed to evaluate the adherence to Mediterranean diet (MD) in a large population of LT recipients. Methods: The present multicenter study was developed in clinically stable, liver transplanted patients, from June to September 2021. Patients completed a survey about adherence to MD, Quality of Life (QoL), sport, and employment. To analyze the correlations, we computed Pearson's coefficients; while to compare subgroups, independent samples t-tests and ANOVAs. We used a multivariable logistic regression analysis to find the predictors of impaired adherence to MD. Results: The questionnaire was administered to 511 patients. They were males in 71% of cases with a mean age of 63.1 years (SD±10.8). LT recipients coming from central Italy displayed higher adherence to the MD (M=11.10±1.91) than patients from northern (M=9.94±2.28, P<0.001) or southern Italy (M=10.04±2.16, P<0.001). Patients from central Italy showed a significantly higher consumption of fruit, vegetables, legumes, cereals, olive oil, fish and a significantly lower intake of dairy products than patients resident in the other Italian areas. At multivariate analysis, recipients from central Italy were 3.8 times more likely to report adherence to the MD. Patients with a high physical health score were more adherent to MD, as well as patients transplanted at an earlier time. Conclusions: We demonstrated that place of stay, time from transplant and physical dimension of QoL significantly influences the adherence to MD. Continuous information campaigns about a correct diet and lifestyle would be necessary.

2023 - Human microglia synthesize neurosteroids to cope with rotenone-induced oxidative stress [Articolo su rivista]
Lucchi, Chiara; Codeluppi, Alessandro; Filaferro, Monica; Vitale, Giovanni; Rustichelli, Cecilia; Avallone, Rossella; Mandrioli, Jessica; Biagini, Giuseppe
abstract

We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone. Here, we evaluated whether neurosteroids could be produced and altered in response to rotenone by the human microglial clone 3 (HMC3) cell line. To this aim, HMC3 cultures were exposed to rotenone (100 nM) and neurosteroids were measured in the culture medium by liquid chromatography with tandem mass spectrometry. Microglia reactivity was evaluated by measuring interleukin 6 (IL-6) levels, whereas cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After 24 hours (h), rotenone increased IL-6 and reactive oxygen species levels by approximately +37% over the baseline, without affecting cell viability; however, microglia viability was significantly reduced at 48 h (p < 0.01). These changes were accompanied by the downregulation of several neurosteroids, including pregnenolone, pregnenolone sulfate, 5α-dihydroprogesterone, and pregnanolone, except for allopregnanolone, which instead was remarkably increased (p < 0.05). Interestingly, treatment with exogenous allopregnanolone (1 nM) efficiently prevented the reduction in HMC3 cell viability. In conclusion, this is the first evidence that human microglia can produce allopregnanolone and that this neurosteroid is increasingly released in response to oxidative stress, to tentatively support the microglia's survival.

2022 - Acute cytotoxicity of mineral fibres observed by time-lapse video microscopy [Articolo su rivista]
Di Giuseppe, D.; Scarfi, S.; Alessandrini, A.; Bassi, A. M.; Mirata, S.; Almonti, V.; Ragazzini, G.; Mescola, A.; Filaferro, M.; Avallone, R.; Vitale, G.; Scognamiglio, V.; Gualtieri, A. F.
abstract

Inhalation of mineral fibres is associated with the onset of an inflammatory activity in the lungs and the pleura responsible for the development of fatal malignancies. It is known that cell damage is a necessary step for triggering the inflammatory response. However, the mechanisms by which mineral fibres exert cytotoxic activity are not fully understood. In this work, the kinetics of the early cytotoxicity mechanisms of three mineral fibres (i.e., chrysotile, crocidolite and fibrous erionite) classified as carcinogenic by the International Agency for Research on Cancer, was determined for the first time in a comparative manner using time-lapse video microscopy coupled with in vitro assays. All tests were performed using the THP-1 cell line, differentiated into M0 macrophages (M0-THP-1) and exposed for short times (8 h) to 25 μg/mL aliquots of chrysotile, crocidolite and fibrous erionite. The toxic action of fibrous erionite on M0-THP-1 cells is manifested since the early steps (2 h) of the experiment while the cytotoxicity of crocidolite and chrysotile gradually increases during the time span of the experiment. Chrysotile and crocidolite prompt cell death mainly via apoptosis, while erionite exposure is also probably associated to a necrotic-like effect. The potential mechanisms underlying these different toxicity behaviours are discussed in the light of the different morphological, and chemical-physical properties of the three fibres.

2022 - Disclosing the Antioxidant and Neuroprotective Activity of an Anthocyanin-Rich Extract from Sweet Cherry (Prunus avium L.) Using In Vitro and In Vivo Models [Articolo su rivista]
Filaferro, M.; Codeluppi, A.; Brighenti, V.; Cimurri, F.; Gonzalez-Paramas, A. M.; Santos-Buelga, C.; Bertelli, D.; Pellati, F.; Vitale, G.
abstract

In this study, an autochthonous variety of sweet cherry (Prunus avium L.), namely “Moretta di Vignola”, was processed to prepare extracts rich in polyphenols, which were characterized by high-performance liquid chromatography (HPLC) separation coupled to UV/DAD and ESI-MSn analysis. Then, a sweet cherry anthocyanin-rich extract (ACE) was prepared, fully characterized and tested for its activity against Parkinson’s disease (PD) in cellular (BV2 microglia and SH-SY5Y neuroblastoma) and in Drosophila melanogaster rotenone (ROT)-induced model. The extract was also evaluated for its antioxidant activity on Caenorhabditis elegans by assessing nematode resistance to thermal stress. In both cell lines, ACE reduced ROT-induced cell death and it decreased, alone, cellular reactive oxygen species (ROS) content while reinstating control-like ROS values after ROT-induced ROS rise, albeit at different concentrations of both compounds. Moreover, ACE mitigated SH-SY5Y cell cytotoxicity in a non-contact co-culture assay with cell-free supernatants from ROT-treated BV-2 cells. ACE, at 50 µg/mL, ameliorated ROT (250 µM)-provoked spontaneous (24 h duration) and induced (after 3 and 7 days) locomotor activity impairment in D. melanogaster and it also increased survival and counteracted the decrease in fly lifespan registered after exposure to the ROT. Moreover, heads from flies treated with ACE showed a non-significant decrease in ROS levels, while those exposed to ROT markedly increased ROS levels if compared to controls. ACE + ROT significantly placed the ROS content to intermediate values between those of controls and ROT alone. Finally, ACE at 25 µg/mL produced a significant increase in the survival rate of nematodes submitted to thermal stress (35 °C, 6–8 h), at the 2nd and 9th day of adulthood. All in all, ACE from Moretta cherries can be an attractive candidate to formulate a nutraceutical product to be used for the prevention of oxidative stress-induced disorders and related neurodegenerative diseases.

2021 - In vitro toxicity of fibrous glaucophane [Articolo su rivista]
Gualtieri, A. F.; Zoboli, A.; Filaferro, M.; Benassi, M.; Scarfi, S.; Mirata, S.; Avallone, R.; Vitale, G.; Bailey, M.; Harper, M.; Di Giuseppe, D.
abstract

The health hazard represented by the exposure to asbestos may also concern other minerals with asbestos-like crystal habit. One of these potentially hazardous minerals is fibrous glaucophane. Fibrous glaucophane is a major component of blueschist rocks of California (USA) currently mined for construction purposes. Dust generated by the excavation activities might potentially expose workers and the general public. The aim of this study was to determine whether fibrous glaucophane induces in vitro toxicity effects on lung cells by assessing the biological responses of cultured human pleural mesothelial cells (Met-5A) and THP-1 derived macrophages exposed for 24 h and 48 h to glaucophane fibres. Crocidolite asbestos was tested for comparison. The experimental configuration of the in vitro tests included a cell culture without fibres (i.e., control), cell cultures treated with 50 μg/mL (i.e., 15.6 μg/cm2) of crocidolite fibres and 25-50−100 μg/mL (i.e., 7.8−15.6–31.2 μg/cm2) of glaucophane fibres. Results showed that fibrous glaucophane may induce a decrease in cell viability and an increase in extra-cellular lactate dehydrogenase release in the tested cell cultures in a concentration dependent mode. Moreover, it was found that fibrous glaucophane has a potency to cause oxidative stress. The biological reactivity of fibrous glaucophane confirms that it is a toxic agent and, although it apparently induces lower toxic effects compared to crocidolite, exposure to this fibre may be responsible for the development of lung diseases in exposed unprotected workers and population.

2020 - BV-2 Microglial Cells Respond to Rotenone Toxic Insult by Modifying Pregnenolone, 5alpha-Dihydroprogesterone and Pregnanolone Level [Articolo su rivista]
Avallone, Rossella; Lucchi, Chiara; Puja, Giulia; Codeluppi, Alessandro; Filaferro, Monica; Vitale, Giovanni; Rustichelli, Cecilia; Biagini, Giuseppe
abstract

Neuroinflammation, whose distinctive sign is the activation of microglia, is supposed to play a key role in the development and progression of neurodegenerative diseases. The aim of this investigation was to determine levels of neurosteroids produced by resting and injured BV-2 microglial cells. BV-2 cells were exposed to increasing concentrations of rotenone to progressively reduce their viability by increasing reactive oxygen species (ROS) production. BV-2 cell viability was significantly reduced 24, 48 and 72 h after rotenone (50–1000 nM) exposure. Concomitantly, rotenone (50–100 nM) determined a dose-independent augmentation of ROS production. Then, BV-2 cells were exposed to a single, threshold dose of rotenone (75 nM) to evaluate the overtime release of neurosteroids. In particular, pregnenolone, pregnenolone sulfate, progesterone, 5alpha-dihydroprogesterone (5-DHP), allopregnanolone, and pregnanolone, were quantified in the culture medium by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. BV-2 cells synthesized all the investigated neurosteroids and, after exposure to rotenone, 5DHP and pregnanolone production was remarkably increased. In conclusion, we found that BV-2 cells not only synthesize several neurosteroids, but further increase this production following oxidative damage. Pregnanolone and 5alpha-DHP may play a role in modifying the progression of neuroinflammation in neurodegenerative diseases.

2020 - CCAP regulates feeding behavior via the NPF pathway in Drosophila adults [Articolo su rivista]
Williams, M. J.; Akram, M.; Barkauskaite, D.; Patil, S.; Kotsidou, E.; Kheder, S.; Vitale, G.; Filaferro, M.; Blemings, S. W.; Maestri, G.; Hazim, N.; Vergoni, A. V.; Schioth, H. B.
abstract

The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive peptide (CCAP)-expressing neurons in Drosophila adults regulate feeding behavior and metabolism. Notably, loss of CCAP, or knocking down the CCAP receptor (CCAP-R) in 2 dorsal median neurons, inhibits the release of neuropeptide F (NPF), which regulates feeding behavior. Furthermore, under starvation conditions, flies normally have an increased sensitivity to sugar; however, loss of CCAP, or CCAP-R in 2 dorsal median NPF neurons, inhibited sugar sensitivity in satiated and starved flies. Separate from its regulation of NPF signaling, the CCAP peptide also regulates triglyceride levels. Additionally, genetic and optogenetic studies demonstrate that CCAP signaling is necessary and sufficient to stimulate a reflexive feeding behavior, the proboscis extension reflex (PER), elicited when external food cues are interpreted as palatable. Dopaminergic signaling was also sufficient to induce a PER. On the other hand, although necessary, NPF neurons were not able to induce a PER. These data illustrate that the CCAP peptide is a central regulator of feeding behavior and metabolism in adult flies, and that NPF neurons have an important regulatory role within this system.

2019 - Structure Model and Toxicity of the Product of Biodissolution of Chrysotile Asbestos in the Lungs [Articolo su rivista]
Gualtieri, A. F.; Lusvardi, G.; Pedone, A.; Di Giuseppe, D.; Zoboli, A.; Mucci, A.; Zambon, A.; Filaferro, M.; Vitale, G.; Benassi, M.; Avallone, R.; Pasquali, L.; Lassinantti Gualtieri, M.
abstract

Asbestos is a commercial term indicating six natural silicates with asbestiform crystal habit. Of these, five are double-chain silicates (amphibole) and one is a layer silicate (serpentine asbestos or chrysotile). Although all species are classified as human carcinogens, their degree of toxicity is still a matter of debate. Amphibole asbestos species are biopersistent in the human lungs and exert their chronic toxic action for decades, whereas chrysotile is not biopersistent and transforms into an amorphous silica structure prone to chemical/physical clearance when exposed to the acidic environment created by the alveolar macrophages. There is evidence in the literature of the toxicity of chrysotile, but its limited biopersistence is thought to explain the difference in toxicity with respect to amphibole asbestos. To date, no comprehensive model describing the toxic action of chrysotile in the lungs is available, as the structure and toxic action of the product formed by the biodissolution of chrysotile are unknown. This work is aimed at fulfilling this gap and explaining the toxic action in terms of structural, chemical, and physical properties. We show that chrysotile's fibrous structure induces cellular damage, mainly through physical interactions. Based on our previous work and novel findings, we propose the following toxicity model: inhaled chrysotile fibers exert their toxicity in the alveolar space by physical and biochemical action. The fibers are soon leached by the intracellular acid environment into a product with residual toxicity, and the dissolution process liberates toxic metals in the intracellular and extracellular environment.

2018 - In vitro and in vivo characterization of the bifunctional μ and δ opioid receptor ligand UFP-505 [Articolo su rivista]
Dietis, N.; Niwa, H.; Tose, R.; Mcdonald, J.; Ruggieri, V.; Filaferro, M.; Vitale, G.; Micheli, L.; Ghelardini, C.; Salvadori, S.; Calo', Giovanni Fabrizio; Guerrini, Remo; Rowbotham, D. J.; Lambert, D. G.
abstract

Background and Purpose: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reducing side-effects. We have evaluated the mixed μ opioid receptor agonist/ δ opioid receptor antagonist UFP-505 in vitro and in vivo. Experimental Approach: We measured receptor density and function in single μ, δ and μ /δ receptor double expression systems. GTPγ35S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments, we collected tissues to measure receptor densities. Key Results: UFP-505 bound to μ receptors with full agonist activity and to δ receptors as a low efficacy partial agonist At μ, but not δ receptors, UFP-505 binding recruited arrestin. Unlike morphine, UFP-505 treatment internalized μ receptors and there was some evidence for internalization of δ receptors. Similar data were obtained in a μ /δ receptor double expression system. In rats, acute UFP-505 or morphine, injected intrathecally, was antinociceptive. In tissues harvested from these experiments, μ and δ receptor density was decreased after UFP-505 but not morphine treatment, in agreement with in vitro data. Both morphine and UFP-505 induced significant tolerance. Conclusions and Implications: In this study, UFP-505 behaved as a full agonist at μ receptors with variable activity at δ receptors. This bifunctional compound was antinociceptive in rats after intrathecal administration. In this model, dual targeting provided no advantages in terms of tolerance liability. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

2017 - Effects of [Nphe1, Arg14, Lys15] N/OFQ-NH2 (UFP-101), a potent NOP receptor antagonist, on molecular, cellular and behavioural alterations associated with chronic mild stress. [Articolo su rivista]
Vitale, Giovanni; Filaferro, Monica; Micioni Di Bonaventura, Maria Vittoria; Ruggieri, Valentina; Cifani, Carlo; Guerrini, Remo; Simonato, Michele; Zucchini, Silvia
abstract

The present study investigated the effect of [Nphe1] Arg14, Lys15-N/OFQ-NH2 (UFP-101), a selective NOP receptor antagonist, in chronic mild stress (CMS) in male Wistar rats. NOP receptor antagonists were reported to elicit antidepressant-like effects in rodents. Our aim was to investigate UFP-101 effects on CMS-induced anhedonia and impairment of hippocampal neurogenesis. UFP-101 (10 nmol/rat intracerebroventricularly) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals from the second week of treatment. UFP-101 also reversed stress effects in forced swimming test and in open field. Fluoxetine (10 mg/kg intraperitoneally) produced similar effects. Moreover, we investigated whether UFP-101 could affect CMS-induced impairment in hippocampal cell proliferation and neurogenesis, and in fibroblast growth factor (FGF-2) expression. Our data confirm that CMS reduced neural stem cell proliferation and neurogenesis in adult rat hippocampus. Chronic UFP-101 treatment did not affect the reduced proliferation (bromodeoxyuridine-positive cells) observed in stressed animals. However, UFP-101 increased the number of doublecortin-positive cells, restoring neurogenesis. Finally, UFP-101 significantly increased FGF-2 expression, reduced by CMS. These findings support the view that blockade of NOP receptors produces antidepressant-like effects in CMS associated with positive effects on neurogenesis and FGF-2 expression. Therefore, NOP receptors may represent a target for innovative antidepressant drugs.

2015 - Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization [Articolo su rivista]
Chen, Peiwen; Cescon, Matilde; Zuccolotto, Gaia; Nobbio, Lucilla; Colombelli, Cristina; Filaferro, Monica; Vitale, Giovanni; Feltri, M. Laura; Bonaldo, Paolo
abstract

Macrophages contribute to peripheral nerve regeneration and produce collagen VI, an extracellular matrix protein involved in nerve function. Here, we show that collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of collagen VI, whereas lack of collagen VI in Col6a1(-/-) mice delays peripheral nerve regeneration. In vitro studies demonstrated that collagen VI promotes macrophage migration and polarization via AKT and PKA pathways. Col6a1(-/-) macrophages exhibit impaired migration abilities and reduced antiinflammatory (M2) phenotype polarization, but are prone to skewing toward the proinflammatory (M1) phenotype. In vivo, macrophage recruitment and M2 polarization are impaired in Col6a1(-/-) mice after nerve injury. The delayed nerve regeneration of Col6a1(-/-) mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function.

2014 - Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviors: involvement of the serotonergic system [Articolo su rivista]
Filaferro, Monica; Ruggieri, Valentina; Novi, C; Calò, G; Cifani, C; Micioni Di Bonaventura, M. V; Sandrini, Maurizio; Vitale, Giovanni
abstract

Nociceptin/orphanin FQ (N/OFQ) acts as an anxiolytic-like agent in the rat and behaves as a functional antagonist of corticotropin-releasing factor (CRF) due to its ability to oppose CRF biological actions. In response to stress, CRF triggers changes in neurotransmitter systems including serotonin (5-HT). The role of 5-HT1A receptor in anxiety has been supported by preclinical and clinical studies. The present study investigated the possible functional antagonism between N/OFQ (1nmol/rat) and CRF (0.2nmol/rat) in anxiety-related conditions in rats, using elevated plus maze and defensive burying tests, in order to confirm previous literature results. Moreover, possible changes in the serotonergic system were studied in areas rich of serotonergic neurons: frontal cortex and pons. In both tests N/OFQ showed anxiolytic-like effects while CRF displayed anxiogenic-like effects. N/OFQ before CRF treatment counteracted the anxiogenic-like effects evoked by CRF. In frontal cortex, N/OFQ significantly decreased 5-HT levels but did not modify the hydroxyindoleacetic acid (5-HIAA) ones; CRF modified neither 5-HT nor 5-HIAA content but counteracted changes induced by N/OFQ alone. In pons, N/OFQ induced no change in serotonergic activity while CRF significantly decreased 5-HT levels and increased 5-HIAA content. The two peptides' combination reinstated serotonergic parameters to controls. In frontal cortex, N/OFQ increased the 5HT1A receptor density but reduced its affinity, while CRF alone did not induce any change. In pons, CRF decreased 5HT1ABmax and KD whereas N/OFQ was ineffective. All biochemical modifications were reverted by N/OFQ plus CRF treatment. The present study confirms that N/OFQ counteracts CRF anxiogenic-like effects in the behavioral tests evaluated. These effects may involve central serotonergic mechanisms since N/OFQ plus CRF induces a reversion of serotonergic changes provoked by single peptide. Our data support the hypothesis that N/OFQ may behave as functional CRF antagonist, this action being of interest for the treatment of anxiety disorders.

2013 - Neuropeptide S stimulates human monocyte chemotaxis via NPS receptor activation. [Articolo su rivista]
Filaferro, Monica; Novi, Chiara; Ruggieri, Valentina; Genedani, Susanna; Alboni, Silvia; Malagoli, Davide; Caló, G; Guerrini, R; Vitale, Giovanni
abstract

Neuropeptide S (NPS) produces several biological actions by activating a formerly orphan GPCR, now named NPS receptor (NPSR). It has been previously demonstrated that NPS stimulates murine leukocyte chemotaxis in vitro. In the present study we investigated the ability of NPS, in comparison with the proinflammatory peptide formyl-Met-Leu-Phe (fMLP), to stimulate human monocyte chemotaxis. At a concentration of 10(-8)M fMLP significantly stimulated chemotaxis. NPS produced a concentration dependent chemotactic action over the concentration range 10(-12) to 10(-5)M. The NPSR antagonists [D-Cys((t)Bu)(5)]NPS, [(t)Bu-D-Gly(5)]NPS and SHA 68 were used to pharmacologically characterize NPS action. Monocyte chemoattractant effect of NPS, but not fMLP, was completely blocked by either peptide antagonists or SHA with the nonpeptide molecule being more potent. None of the NPSR antagonists modified per se random cell migration. Thus, the present study demonstrated that NPS is able to stimulate human monocyte chemotaxis and that this effect is entirely due to selective NPSR activation.

2012 - Effect of Hypericum perforatum Extract in an Experimental Model of Binge Eating in Female Rats. [Articolo su rivista]
Micioni Di Bonaventura, Mv; Vitale, Giovanni; Massi, M; Cifani, C.
abstract

Purpose. The present study evaluated the effect of Hypericum perforatum dry extract in an experimental model of binge eating (BE). Methods. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding and acute stress on the test day (day 25). Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. Hypericum perforatum dry extract was given by gavage. Results. Only rats exposed to both food restrictions and stress exhibited BE. The doses of 250 and 500 mg/kg of Hypericum perforatum extract significantly reduced the BE episode, while 125 mg/kg was ineffective. The same doses did not affect HPF intake in the absence of BE. The dose of 250 mg/kg did not significantly modify stress-induced increase in serum corticosterone levels, suggesting that the effect on BE is not due to suppression of the stress response The combined administration of 125 mg/kg of Hypericum perforatum together with Salidroside, active principle of Rhodiola rosea, produced a synergic effect on BE. Conclusions. The present results indicate for the first time that Hypericum perforatum extracts may have therapeutic properties in bingeing-related eating disorders.

2012 - [tBu-D-Gly5]NPS, a pure and potent antagonist of the neuropeptide S receptor: in vitro and in vivo studies. [Articolo su rivista]
Ruzza, C; Rizzi, A; Camarda, V; Pulga, A; Marzola, G; Filaferro, Monica; Novi, Chiara; Ruggieri, Valentina; Marzola, E; Vitale, Giovanni; Salvadori, S; Guerrini, R; Calo', G.
abstract

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Recently, the NPSR ligand [(t)Bu-D-Gly(5)]NPS was generated and in vitro characterized as a pure antagonist at the mouse NPSR. In the present study the pharmacological profile of [(t)Bu-D-Gly(5)]NPS has been investigated. [(t)Bu-D-Gly(5)]NPS activity was evaluated in vitro in the calcium mobilization assay at the rat NPSR and in vivo in the locomotor activity and righting reflex tests in mice and in the elevated plus maze and defensive burying assays in rats. In vitro, [(t)Bu-D-Gly(5)]NPS was inactive per se while it inhibited the calcium mobilization induced by 30 nM NPS (pK(B) 7.42). In Schild analysis experiments [(t)Bu-D-Gly(5)]NPS (0.1-10 μM) produced a concentration-dependent rightward shift of the concentration-response curve to NPS, showing a pA(2) value of 7.17. In mouse locomotor activity experiments, supraspinal injection of [(t)Bu-D-Gly(5)]NPS (1-10 nmol) dose dependently counteracted NPS (0.1 nmol) stimulant effects. In the mouse righting reflex assay [(t)Bu-D-Gly(5)]NPS (0.1-10 nmol) fully prevented the arousal-promoting action of the natural peptide (0.1 nmol). Finally, [(t)Bu-D-Gly(5)]NPS (3-30 nmol) was able to completely block NPS (1 nmol) anxiolytic-like actions in rat elevated plus maze and defensive burying assays. Collectively, the present results demonstrated that [(t)Bu-D-Gly(5)]NPS behaves both in vitro and in vivo as a pure and potent NPSR antagonist. This compound represents a novel and useful tool for investigating the pharmacology and neurobiology of the NPS/NPSR system.

2010 - Effect of salidroside, active principle of Rhodiola rosea extract, on binge eating. [Articolo su rivista]
Cifani, C; Micioni Di B., Mv; Vitale, Giovanni; Ruggieri, Valentina; Ciccocioppo, R; Massi, M.
abstract

Stress is a key determinant of binge eating (BE). Since Rhodiola rosea is known to modulate stress responses, its effect in a model of BE was investigated. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding (for 4days 66% of the usual chow intake; for 4days food ad libitum) and acute stress on the test day (day 25). R. rosea dry extract (3% rosavin, 3.12% salidroside) or its active principles were given by gavage 1h before access to HPF. Only rats exposed to both food restrictions and stress exhibited BE in the first 15-60min after the stressful procedure. R. rosea extract 10mg/kg significantly reduced and 20mg/kg abolished the BE episode. R. rosea extract 20mg/kg abolished also stress-induced increase in serum corticosterone levels. The R. rosea active principle salidroside, but not rosavin, at doses present in the extract, dose-dependently reduced or abolished BE for the period in which it was elicited. In conclusion results indicate that R. rosea extracts may have therapeutic properties in bingeing-related eating disorders and that salidroside is the active principle responsible for this effect.

2010 - Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. [Articolo su rivista]
Ruzza, C; Rizzi, A; Trapella, C; Pela', M; Camarda, V; Ruggieri, Valentina; Filaferro, Monica; Cifani, C; Reinscheid, Rk; Vitale, Giovanni; Ciccocioppo, R; Salvadori, S; Guerrini, R; Calo', G.
abstract

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Previous studies demonstrated that the non-peptide molecule SHA 68 acts as a selective NPSR antagonist. In the present study the pharmacological profile of SHA 68 has been further investigated in vitro and in vivo. In cells expressing the mouse NPSR SHA 68 was inactive per se up to 10 μM while it antagonized NPS-stimulated calcium mobilization in a competitive manner showing a pA2 value of 8.06. In the 10–50 mg/kg range of doses, SHA 68 counteracted the stimulant effects elicited by NPS, but not those of caffeine, in mouse locomotor activity experiments. In the mouse righting reflex assay SHA 68 fully prevented the arousal-promoting action of the peptide. The anxiolytic-like effects of NPS were slightly reduced by SHA 68 in the mouse open field, fully prevented in the rat elevated plus maze and partially antagonized in the rat defensive burying paradigm. Finally, SHA 68 was found poorly active in antagonizing the NPS inhibitory effect on palatable food intake in rats. In all assays SHA 68 did not produce any effect per se. In conclusion, the present study demonstrated that SHA 68 behaves as a selective NPSR antagonist that can be used to characterize the in vivo actions of NPS. However the usefulness of this research tool is limited by its poor pharmacokinetic properties.

2010 - Glutamate-mediated astrocyte-to-neuron signaling in the rat dorsal horn [Articolo su rivista]
Bardoni, Rita; Ghirri, Alessia; Micaela, Zonta; Betelli, Chiara; Vitale, Giovanni; Ruggieri, Valentina; Sandrini, Maurizio; Giorgio, Carmignoto
abstract

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandinsand neurotrophins, microglia and astrocytes are proposed to be involved in nociceptivetransmission, especially in conditions of persistent, pathological pain. The specificaction on dorsal horn neurons of agents released from astrocytes, such as glutamate, hasbeen, however, poorly investigated. By using patch-clamp and confocal microscopecalcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsalhorn lamina II neurons following astrocyte activation. Results obtained revealed thatstimuli that triggered Ca2+ elevations in astrocytes, such as the purinergic receptoragonist BzATP and low extracellular Ca2+, induce in lamina II neurons slow inwardcurrents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons fromother central nervous system regions, these currents: i) are insensitive to TTX, ii) areblocked by the NMDA receptor antagonist D-AP5, iii) lack an AMPA component, andiv) have slow rise and decay times. Ca2+ imaging also revealed that astrocytic glutamateevokes NMDAR-mediated episodes of synchronous activity in groups of substantiagelatinosa neurons. Importantly, in a model of peripheral inflammation, thedevelopment of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDARmediatedastrocyte-to-neuron signaling thus represents a novel pathway that maycontribute to the control of central sensitization in pathological pai

2010 - The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist and involves the serotonergic system in rats [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Filaferro, Monica; Frigeri, Claudio; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

Combinations of non steroidal anti-inflammatory drugs (NSAIDs) and cannabinoids are promising because of their potential synergistic effects in analgesia, resulting in a reduction in dosage and minimizing adverse reactions. The analgesic effect of Acetylsalicylic acid (ASA), probably due to a central mechanism, also implicates changes in the central monoaminergic system. Therefore, we decided to evaluate the antinociceptive interaction between the CB1 receptor agonist, HU210, and ASA in tests involving central pain in rats as well as the implication of the central serotonergic system thereon.

2009 - Chronic treatment with the selective NOP receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats [Articolo su rivista]
Vitale, Giovanni; Ruggieri, Valentina; Filaferro, Monica; Frigeri, Claudio; Alboni, Silvia; Tascedda, Fabio; Brunello, Nicoletta; Guerrini, R; Cifani, C; Massi, M.
abstract

Introduction The present study was designed to assess the antidepressant effects of UFP-101, a selective nociceptin/orphanin FQ peptide (NOP) receptor antagonist, in a validated animal model of depression: the chronic mild stress (CMS). Materials and methods and Results UFP-101 (5, 10 and 20 nmol/rat; i.c.v., once a day for 21 days) dose- and time-dependently reinstated sucrose consumption in stressed animals without affecting the same parameter in non-stressed ones. In the forced swimming test, UFP-101 reduced immobility of stressed rats from day 8 of treatment. After a 3-week treatment, rats were killed for biochemical evaluations. UFP-101 abolished increase in serum corticosterone induced by CMS and reverted changes in central 5-HT/5-HIAA ratio. The behavioural and biochemical effects of UFP-101 mimicked those of imipramine, the reference antidepressant drug, administered at the dose of 15 mg/kg (i.p.). Co-administration of nociceptin/orphanin FQ (5 nmol/rat, from day 12 to 21) prevented the effects of UFP-101. Brain-derived neurotrophic factor mRNA and protein in hippocampus were not reduced by CMS nor did UFP-101 modify these parameters. Discussion and Conclusion This study demonstrated that chronic treatment with UFP-101 produces antidepressant-like effects in rats subjected to CMS supporting the proposal that NOP receptors represent a candidate target for the development of innovative antidepressant drugs.

2008 - ANXIOLYTIC LIKE EFFECT OF NEUROPEPTIDE S IN THE RAT DEFENSIVE BURYING. [Articolo su rivista]
Vitale, Giovanni; Filaferro, Monica; Ruggieri, Valentina; S., Pennella; Frigeri, Claudio; A., Rizzi; R., Guerrini; G., Calò
abstract

Neuropeptide S (NPS) has been recently identified as the endogenous ligand of a previously orphan G-protein-coupled receptor now named NPSR. Both NPS and its receptor are expressed in the brain, where they modulate different functions. In particular, it has been demonstrated that intracerebroventricular (i.c.v.) injection of NPS in rodents increases wakefulness and promotes anxiolytic-like effects. In the present study we used the defensive burying (DB) test in rats to further investigate the action of human NPS (0.1–10 nmol, i.c.v.) on anxiety-related behaviors. Diazepam (1.5 mg/kg, i.p.) and caffeine (20 mg/kg, i.p.) were used in parallel experiments as standard anxiolytic and anxiogenic drugs, respectively. None of the tested drugs produced statistical differences in the latency to contact the probe, burying behavior latency, number of shocks received or immobility/freezing duration. Caffeine increased cumulative burying behavior and the buried bedding height in a statistically significant manner thus promoting anxiogenic like effects. Opposite results were obtained with diazepam that significantly reduced these behavioral parameters. The anxiolytic-like action of diazepam was mimicked by NPS that reduced cumulative burying behavior in a dose dependent manner. Collectively, robust anxiolytic-like effects were recorded in response to NPS in the DB test. These results are of particular interest since the outcome of this assay is marginally influenced by drug effects on locomotor activity. In conclusion, we provide further evidence that NPS evokes genuine anxiolytic-like effects in the rat; therefore NPSR selective agonists are worthy of development as innovative drugs for the treatment of anxiety disorders.

2008 - Differential involvement of opioidergic and serotoninergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

It is recognized that paracetamol undergoes ametabolic transformation to N-arachydonylphenolamine(AM404), a CB1 receptor ligand and anandamide uptakeinhibitor. Using hot-plate and paw pressure tests, wedecided to establish whether AM404 may act throughopioidergic and serotonergic mechanisms. Thus, we pretreatedrats with opioid μ1 (naloxonazine) and κ (MR2266)or 5-HT1A (NAN-190), 5-HT2 (ketanserin), and 5-HT3(ondansetron) receptor antagonists. We investigated thepossible changes in 5-hydroxyindoleacetic acid/serotoninratio in the frontal cortex and pons. The antinociceptiveeffect of AM404 (10 mg/kg, intrapertoneally) or paracetamol(400 mg/kg, intrapertoneally) in either test wasabolished by naloxonazine or MR2266. Ondansetronprevented AM404 activity; NAN-190 and ketanserin wereineffective. Ketanserin antagonized paracetamol activity;NAN-190 and ondansetron were inactive. AM404 did notchange serotonergic activity, while paracetamol decreasedserotonin turnover. The diverse antinociceptive potency ofthe compounds might be explained by the differentinfluence on the serotonergic system, despite a similarinvolvement of opioidergic one.

2007 - Effect of acute and repeated administration of paracetamol on opioidergic and serotonergic systems in rats. [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Ruggieri, Valentina; Pini, Luigi Alberto
abstract

Objective and design: We investigated the antinociceptiveeffect of paracetamol or morphine after repeatedadministration and the changes in the characteristics of centralμ-, κ- and 5-HT2 receptors.Treatment: Male rats were injected twice a day for sevendays with paracetamol (400 mg/kg, i. p.) or morphine (5 mg/kg, s. c.).Methods: The antinociceptive effect was evaluated 30 minafter single and multiple doses of paracetamol and morphinethrough the hot-plate test. Binding techniques were used toevaluate the receptor characteristics in the frontal cortex.Results: Both paracetamol and morphine induced an antinociceptiveeffect on day 1 but only paracetamol maintainedthis effect for seven days while morphine did not.The number of μ-opioid receptors decreased on days 1, 3,and 7 by a similar percentage after paracetamol administration(by 29, 31 and 34 %, respectively), while morphineproduced a progressive decrease in comparison with controls(by 37, 49 and 60 %, respectively) and κ-opioid receptorswere unaffected. Both drugs similarly decreased the 5-HT2receptor number on all days of treatment (by about 30 %).Conclusions: The opioidergic and serotonergic systems areinvolved in different ways in the induction and maintenanceof antinociception after paracetamol or morphine treatment.

2006 - Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats [Articolo su rivista]
Vitale, Giovanni; Arletti, Rossana; Ruggieri, Valentina; Cifani, C; Massi, M.
abstract

Different reports suggest that nociceptin/orphanin FQ (N/OFQ) may have either anxiolytic- or anxiogenic-like effect in rodents. Since N/OFQ elicits hypolocomotion, which undergoes rapid tolerance, and hypolocomotion may be associated to emotional consequences, the present study was designed to investigate the effect of N/OFQ on anxiety after development of tolerance to its hypolocomotor effect. The effect of single or double intracerebroventricular (i.c.v.) injection of N/OFQ was evaluated on anxiety-related behaviors in rats, in the elevated plus maze (EPM) and conditioned defensive burying (CDB) tests. After single administration, N/OFQ displayed an anxiogenic-like pattern of response on the elevated plus maze but hypolocomotion was also observed. Conversely, in the CDB test, N/OFQ induced a clear-cut anxiolytic pattern. To produce tolerance to N/OFQ-induced hypolocomotion the peptide was administered by two i.c.v. injections separated by 120 min; in these conditions it decreased the expression of anxiety-related behaviors in both tests without affecting locomotor activity. The nociceptin/orphanin FQ peptide (NOP) receptor antagonist UFP-101 significantly reduced the effects of N/OFQ to control values in either tests. Corticosterone levels were significantly increased after a single N/OFQ administration (not in a dose-dependent manner) but this increase did not reach significance after double administration (1 nmol/rat). Our results support the idea that N/OFQ may act as an anxiolytic-like agent in the rat; the apparent anxiogenic-like effect observed following its single administration in the EPM may be consequent to its, effect on locomotion. (c) 2006 Elsevier Inc. All rights reserved.

2005 - Acute noise stress analgesia in relation to 5-HT2 and mu-opioid receptor changes in the frontal cortex of young mice [Articolo su rivista]
Vitale, Giovanni; Arletti, Rossana; Sandrini, Maurizio
abstract

A number of studies have reported that exposure to stress provoked behavioural changes, including analgesia, in rodents. Differences have been observed in these responses to different types of stress and a link between hormones and neurotransmitters proposed. We studied the effect of acute noise stress on nociception and the possible changes in the serotonergic and opioidergic systems in young mice of both sexes. Naloxone pretreatment was also investigated. Noise stress was produced by a sound source, nociception was measured by the hot-plate test and binding characteristics were evaluated by a radioligand binding technique using membrane preparation from the total frontal cortex. Acute noise stress provoked an antinociceptive effect, associated with an increase in plasma corticosterone levels, a decrease in the number of 5-HT2 receptors in stressed male and female mice and a decrease in the number of mu receptors in both sexes. The behavioural and biochemical effects were antagonized by 1 mg/kg of naloxone. Acute noise stress behaves like other types of stress on nociception. The opioidergic system seems to be involved in this behaviour but also the serotonergic system may play a role. Sex differences were detected in the number of 5-HT2 and mu receptors between male and female mice not subjected to stress, while the percentage decrease in 5-HT2 and mu receptors did not differ significantly between the two sexes.

2005 - Nociceptin/orphanin FQ prevents the antinociceptive action of paracetamol on the rat hot plate test [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto; G., Lopetuso; P., Romualdi; S., Candeletti
abstract

Nociceptin/orphanin FQ (N/OFQ) is involved in many behavioural patterns; in particular. it exerts a modulating effect on nociception. Like other proposed antiopiates, nociceptin/orphanin FQ has been shown to have analgesic, hyperalgesic as well as antianalgesic properties. Among the various effects proposed on nociceptive sensitivity at supraspinal level, the antagonistic activity toward morphine analgesia seems to be of interest. Therefore, we decided to investigate whether nociceptin/orphanin FQ and [Arg(14), Lys(15)] nociceptin/orphanin FQ (R-K, a nociceptin analogue) can have the same effect on the analgesia produced by nonopioid analgesics. in this study. we examined the antianalgesic effect of nociceptin/orphanin FQ and its analogue R-K on paracetamol-induced analgesia and evaluated by means of the hot plate test in rats. Nociceptin/orphanin FQ was intracerebroventricularly administered, anti. after 5 min, a dose of 400 mg/kg paracetamol was injected intraperitoneally, 30 min before the hot plate test. Nociceptin/orphanin FQ and R-K showed a dose-dependent antagonism on the antinociceptive effect of paracetamol, and the activity of both drugs was significantly reduced by the antagonist [Nphe(1)] Arg(14), Lys(15)-N/OFQ-NH2 (UFP-101). These data indicate that nociceptin/orphanin FQ and R-K have an antianalgesic effect on the analgesia produced by a nonopioid analgesic drug, like paracetamol, that seems to develop within the brain.

2004 - Serotonergic and opiatergic modifications induced by paracetamol as a model for daily chronic headache with analgesic overuse [Abstract in Rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

The chronic use of analgesic compounds may contribute to the chronicization of headache. It has been proposed that these headaches associated with daily drug use are due to a rebound effect in a vicious circle drug-headache–drug that mimics drug abuse (Post RM, Silberstein SD, Neurology; 44: 37-4,1994).There are several models to study experimental headaches in relation to acute antimigraine therapy (DeVries et al, Europ J Pharmacol 375: 61-74, 1999), whereas are lacking animal modelsf or daily chronic headache.Paracetamol is a drug widely used to treat headache, and often used in chronic headache sufferers. To explore the possible influence of this drug we performed a study to evaluate the effects of this drug on serotonergic and opiatergic systems in the rat brain after a sub-chronic administration.7 male Wistar rats groups of 8 animals were treated for 7 days with paracetamol i.p. at the dose of 400 mg/kg dissolved in a vehicle volume of 10 ml/kg or vehicle. Animals were submitted to hot-plate test every day at time 2,8 and 24 hours after drug administration. After this test one group of animals was sacrificed every day; the day 1 and 7 also control group were killed. Brains were dissected to determine the presence of binding sites for 5HT2 receptors in cerebral cortex by binding 3H-ketanserin and for opiate receptors by competitive binding with 3H-DAMGO.The results were analysed with Student’s test and Mann-Whitney U test for motor activity. Data were expressed as mean } S.E. Motor activity was not different in vehicle or in paracetamol treated rats at days 1 and 7 ( P> 0.05) . The % of MPE in hotplate test was 5.1}3.2 and 4.7}2.5 at day 1 and 7 for vehicle treated rats, and 24.5}8 and 19.7}4.3 at day 1 and 7 for paracetamol treated rats (P<0.05 vs. ctrl). The maximum bindingcapacity (Bmax )for ketanserin in cortical areas was 254}9.7 and 245}10.5 fmol mg/prot at day 1 and 7 respectively (P>0.5).Paracetamol treated rats Bmax was 194}12.3 and 187}21 fmol mg/prot at day 1 and 7 respectively for ketanserin ( p>0.05), and 250}32 and 170}24 fmol mg/prot at day 1 and 7 respectively for DAMGO (P<0.05). Treatment reduced significantly both types of receptor with respect to vehicle.Repeated doses of paracetamol do not induce tolerance in hotplate test. This treatment induces, as expected, a stable reduction of Bmax in cerebral cortex of 5-HT2 and receptors. These receptors were reduced after a week treatment, whereas the antinociceptive activity was maintained. These data suggest that the prolonged antinociceptive effect of paracetamol is linked more to serotonergic than opiatergic system.This lack of tolerance in analgesic effect of paracetamol could be important to explain the choice of this drug by patients suffering from chronic headaches.

2003 - Differential involvement of central 5-HT1B and 5-HT3 receptor subtypes in the antinociceptive effect of paracetamol [Articolo su rivista]
Sandrini, Maurizio; Pini, Luigi Alberto; Vitale, Giovanni
abstract

Objective: We investigated the effect of pre-treatment with ondansetron or CP 93129 (a 5-HT1B agonist) on the antinociceptive activity of paracetamol and the changes in central 5-HT3 receptors induced by paracetamol alone or co-administered with ondansetron. Materials and Subjects: Male Wistar rats (eight per group) were injected with ondansetron (2 and 4 mg/kg s. c.) or CP 93 129 (0.5, 1 and 2 mg/kg s. c.) 15 min before paracetamol (400 mg/kg, i.p.). Methods: Pain threshold was evaluated in the hot-plate or in the paw pressure test 30 min after the last treatment. 5-HT3 receptor binding capacity was measured in the frontal cortex, temporal-parietal cortex and midbrain by means of radioligand binding technique. Statistical analysis was done using ANOVA followed by Student-Newman-Keuls test and 2 X 2 factorial analysis when appropriate. Results: Pre-treatment with ondansetron, at doses of 2 and 4 mg/kg, did not affect the antinociceptive activity of paracetamol in the hot-plate test and in the paw pressure test. Paracetamol did not change the characteristics of 5-HT3 receptors in all the areas investigated. Ondansetron (4 mg/kg s. c) per se significantly increased the 5-HT3 receptor number in the areas used, the effect not being modified by co-administration with paracetamol. On the other hand, CP 93129 (2 mg/kg s. c.) significantly prevented the effect of paracetamol in both algesimetric tests used. Conclusions: Our data indicate that 5-HT1B but not 5-HT3 receptors are involved in the antinociceptive effect of paracetamol in our experimental conditions.

2003 - Panax notoginseng (Burk.) effects on fibrinogen and lipid plasma level in rats fed on a high-fat diet [Articolo su rivista]
Cicero, Afg; Vitale, G.; Savino, G.; Arletti, R.
abstract

Several studies have shown that notoginsenoides improve diastolic function in hypertensive subjects, induce the fibrinolytic system in in vitro models and act as antiproliferative agents on vessel leiomyocytes. Our aim was to evaluate their effect on fibrinogen and lipid plasma levels compared with a well-known HMGCoA reductase inhibitor. Seventy Wistar male adult rats on a fat-enriched diet were treated orally with P. notoginseng pulverized root (43 mg/kg/day or 86 mg/kg/day; 20 animals per group), fluvastatin (3 mg/kg/day; 20 animals) or physiological saline (5 mL/kg/day; 10 animals). The ten rats on a normocaloric diet were also treated with 5 mL/kg/day of physiological saline. After a 28-day treatment, the rats were killed and their blood analysed with standard procedures. Treatment with 43 mg/kg/day of P. notoginseng or 3 mg/kg/day of fluvastatin showed similar activity in decreasing total cholesterol (-23.70%, -19.29%, respectively) and triglycerides (-21.59%, -18.55%). The most evident effect of P. notoginseng was the reduction of fibrinogenaemia in treated rats compared with the control values (-38.10%; p &lt; 0.001), no dose-relationship being shown in this effect. Moreover, no significant variation in HDL cholesterol and glucose levels was observed nor did relevant behavioural changes occur in association with the root intake. Besides a moderate, non dose-related decrease in the plasma lipid levels, P. notoginseng appeared to induce a significant reduction in the rat fibrinogenaemia. Copyright

2002 - Central antinociceptive activity of acetylsalicylic acid is modulated by brain serotonin receptor subtypes [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Male Wistar rats were treated with ondansetron (1 and 2 mg/kg s.c.), ketanserin (0.2, 1 and 5 mg/kg s.c.) or NAN-190 (1, 3 and 5 mg/kg i.p.) 15 min before acetylsalicylic acid (ASA, 400 mg/kg i.p.), and 30 min thereafter the pain threshold was evaluated. The antinociceptive activity of ASA in the hot-plate test was variously affected by ondansetron, ketanserin and NAN-190: at the highest dose (2 mg/kg s.c.) ondansetron abolished it while ketanserin (5 mg/kg s.c.) significantly reduced it, and NAN-190 (1-5 mg/kg) did not significantly modify the effect of ASA. Binding experiments indicate that both ondansetron and ketanserin completely prevented the decrease in the maximum number of 5-HT2 receptors (B-max) provoked by ASA. These data indicate that the central antinociceptive activity of ASA is modulated in a different manner by serotonin receptor antagonists, and that 5-HT2 and 5-HT3 receptors may exert a pivotal role in nociception, alone or in association. Copyright

2002 - Effect of rofecoxib on nociception and the serotonin system in the rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Objective and design: The purpose of the present study was to determine whether the antinociceptive activity of rofecoxib is mediated, at least in part, through changes in the brain serotonergic system. Materials and subjects: Male Wistar rats weighing 180-200 g (groups of eight) were subjected to the hot-plate and formalin tests after rofecoxib, treatment, Cortical areas were removed for serotonin (5-HT) level, 5-HT2 and mu-receptor evaluation. Treatment: Rofecoxib was administered orally at doses of 5, 10, 20 and 50 mg/kg for the time course evaluation in the hot-plate test (30, 60 and 120 min), and at the dose of 10 mg/kg for the formalin test and biochemical determinations. Methods: The tests performed were the hot-plate and the formalin assays. HPLC was used to determine 5-HT levels and radioligand-binding assays were utilized to evaluate the characteristics of 5-HT2 and mu-receptors. The data were analysed by ANOVA or Student's t test. Results: The lowest active dose of rofecoxib in the hot-plate test was 10 mg/kg. The percentage of the maximum possible effect (%MPE) values were: control = 1.7+/-3.4; treated 23.4+/-6.5 (p<6.05). The same dose had a significant effect on both phases of the formalin test. Pretreatment with p-chlorophenylalanine (PCPA) significantly decreased the activity of rofecoxib in the hot-plate test, Rofecoxib treatment increased serotonin levels and decreased the maximum number of 5-HT2 receptors. 5-HT levels (ng/g) were: control = 240.1+/-28.5, rofecoxib = 326.1+/-19.9 in the frontal cortex. The characteristics of mu-receptors did not change. Conclusions: These results suggest that rofecoxib may exert its therapeutic effect, at least in part, through the central serotonergic system. The opioidergic system, on the other hand, seems to be unaffected.

2001 - The effect of paracetamol and morphine combination on dynorphin A levels in the rat brain. [Articolo su rivista]
Sandrini, Maurizio; P., Romualdi; Vitale, Giovanni; G., Morelli; A., Capobianco; Pini, Luigi Alberto; S., Candeletti
abstract

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.

2001 - The effect of Paracetamol on nociception and dynorphin A levels in the rat brain [Articolo su rivista]
Sandrini, Maurizio; P., Romualdi; A., Capobianco; Vitale, Giovanni; G., Morelli; Pini, Luigi Alberto; S., Candeletti
abstract

Male Wistar rats were administered with naloxone (1 mg/kg i,p.) or MR 2266 (5 mg/kg i,p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay, Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex, MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic sistem modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels,

1999 - Gamma-hydroxybutyrate increases gastric emptying in rats [Articolo su rivista]
Poggioli, Rosanna; Vitale, Giovanni; G., Colombo; Ottani, Alessandra; Bertolini, Alfio
abstract

The influence of gamma-hydroxybutyrate (GHB; 10, 50 or 100 mg/kg orally) and of its receptor antagonist, NCS-382 (25, 100 or 200 mg/kg orally, and 100 or 200 mg/kg intraperitoneally), on gastric emptying was studied in rats by measuring the serum level of acetaminophen (20 mg/rat orally, 30 min after GHB or NCS-382) 15, 30, 45 and 60 min after acetaminophen administration, or the amount of acetaminophen still present in the stomach 30 min after its administration. The highest dose of GHB produced a significant increase in 15 and 30 min serum levels of acetaminophen, indicating an acceleration of gastric emptying. A similar result was obtained with the prokinetic drug cisapride, at the oral dose of 2 mg/kg. On the other hand, NCS-382 significantly and dose-dependently reduced the serum levels of acetaminophen at every time of blood sampling, indicating a delay of gastric emptying, an effect confirmed by the amount of acetaminophen still present in the stomach 30 min after administration. Moreover, NCS-382 antagonized the prokinetic effect of GHB. These results may suggest for GHB (and/or possibly for its metabolites) a role in rat stomach motility.

1999 - The potentiation of analgesic activity of paracetamol plus morphine involves the serotonergic system in rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Ottani, Alessandra; Pini, Luigi Alberto
abstract

Objective and Design: We investigated the antinociceptive effect of subactive doses of paracetamol and morphine, given in combination. Material and Treatment: Male Wistar rats were injected with paracetamol (50 or 100 mg/kg i.p.) and morphine (2, 3 or 5 mg/kg s.c.) 10 min later and subjected to algesimetric tests 20 min thereafter. Methods: Pain threshold was evaluated in the hot-plate and formalin tests. 5-HT2 receptor binding capacity and 5-HT and 5-HIAA levels were measured in cortical and pontine areas of the brain by means of radioligand binding technique and by HPLC, respectively. Statistical analysis was done using Student-Neuman-Keul's test and 2 x 2 factorial analysis. Results: Only when given in combination, paracetamol(100 mg/kg) and morphine (2 and 3 mg/kg) were able to evoke an antinociceptive effect in both tests associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors In the cortex. These effects were prevented by i,p. pretreatment with naloxone (I mg/kg i.p,). Conclusions: Subactive doses of paracetamol and morphine exert an analgesic effect when given in combination in the rat and indicate an involvement of both serotonergic and opiatergic systems.

1998 - Acetylsalicyclic acid potentiates the antinociceptive effect of morphine in the rat:involvement of the central serotonergic system. [Articolo su rivista]
Sandrini, Maurizio; Ottani, Alessandra; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Acetylsalicylic acid and morphine are the most widely distributed and most frequently used drugs in the relief of pain, but their analgesic activity has adverse side-effects. Mixtures containing these two drugs are frequently used to relieve mild to moderate pain despite the paucity of relevant experimental evidence so far published. We set out to study the possible antinociceptive effect of a combination of subactive doses of the two drugs in rats. A combination of low doses of acetylsalicylic acid (50 mg/kg i.p.) and morphine (3 mg/kg s.c.) was administered and the pain threshold was evaluated in the hot-plate and formalin tests, and 5-HT2 receptor binding capacity, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in the cortex and pontine areas of the brain. The combination of acetylsalicylic acid and morphine had an analgesic effect in both tests that was associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors in the cortex. These effects were either completely abolished or partially prevented by i.p. pretreatment with naloxone (1 mg/kg i.p.). Our results demonstrate that subactive doses of acetylsalicylic acid and morphine can exert analgesic and biochemical effects when given in combination in the rat and suggest an involvement of serotonergic and opiatergic systems.

1998 - Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain. [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni; Ottani, Alessandra
abstract

Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA

1997 - Effect of liver cirrhosis on the systemic availability of naltrexone in humans [Articolo su rivista]
Bertolotti, Marco; Ferrari, Anna; Vitale, Giovanni; Stefani, M; Trenti, T; Loria, Paola; Carubbi, Francesca; Carulli, Nicola; Sternieri, Emilio
abstract

Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. METHODS: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis. RESULTS: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

1997 - Naloxone-reverisble antinociception by paracetamol in the rat. [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Ottani, A; Sandrini, M.
abstract

Paracetamol at the dose of 400 mg/kg i.p. displayed antinociceptive activity in the hot-plate test and the formalin test. Moreover, it induced a significant increase in brain serotonin (5-HT) concentration and a reduction in the number of 5-HT2 receptors in cortical membranes. Pretreatment with naloxone abolished this antinociceptive activity both in the hot-plate test and in the first phase of the formalin test without affecting the serum concentration of paracetamol. At the same time, naloxone prevented the increase in 5-HT concentration in the central nervous system and the reduction in 5-HT2 receptors in cortical membranes. Competition experiments demonstrated that paracetamol possesses affinity for [3H]naloxone binding sites. The action of morphine on nociception and on the serotonergic system was similar to that of paracetamol; all morphine-induced effects were blocked by naloxone. These data provide further evidence for a central antinociceptive effect of paracetamol and support the hypothesis that paracetamol exerts its antinociceptive activity through the serotonergic system. Moreover, our results point to the relationship between serotonergic and opiatergic systems in the antinociceptive activity of paracetamol.

1997 - Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study [Articolo su rivista]
F. H. J., Wolfhagen; E., Sternieri; W. C. J., Hop; Vitale, Giovanni; Bertolotti, Marco; H. R., van Buuren
abstract

Background &amp; Aims: The efficacy of currently available therapeutic: agents for cholestatic pruritus is often disappointing. The aim of this study was to assess the antipruritic effect of naltrexone, an oral opiate receptor antagonist. Methods: Sixteen patients with pruritus of chronic cholestasis were randomized to receive naltrexone (4-week course of 50 mg naltrexone daily) or placebo, Pruritus, duality of sleep, fatigue (using visual analogue scales), side effects, and liver function were assessed every 2 weeks. Serum naltrexone and 6 beta-naltrexol concentrations in all patients and 5 healthy controls were measured during the first day of naltrexone treatment. Results: Mean changes with respect to baseline were significantly different, in favor of the naltrexone group, for daytime itching (-54% vs, 8%; P &lt; 0.001) and nighttime itching (-44% vs. 7%, P = 0.003). In 4 naltrexone-treated patients, side effects (transient in 3 cases) consistent with an opiate withdrawal syndrome were noted. No deterioration of the underlying disease was observed. Naltrexone and 6 beta-naltrexol levels did not differ between patients and controls, and there was no significant association with treatment response. Conclusions: For patients with cholestatic liver disease and itching, refractory to regular antipruritic therapy, oval naltrexone may be an effective and well-tolerated alternative.

1997 - Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test, ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration, Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA, The serum salicylate concentrations were not affected by pretreatment with naloxone, These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.

1997 - Streptozotocin-induced diabetes provokes changes in serotonin concentration and on 5-HT1A and 5-HT2 receptors in the rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Vergoni, Anna Valeria; Ottani, Alessandra; Bertolini, Alfio
abstract

Since reduced levels of brain serotonin are known to cause behavioural abnormalities, to which diabetics are also prone, we investigated the effect, in rats, of chronic diabetes on brain serotonin concentration and on the numbers of 5-HT1A and 5-HT2 receptors in cerebral cortex and brainstem. Our data show that streptozotocin induces a longlasting hyperglicemia that is associated with a decrease in cerebral concentration of serotonin and with an accompanying increase in the maximum number of 5-HT1A and 5-HT2 receptors in the brain areas studied. Our results may suggest that changes in serotonergic transmission in the CNS play a role in diabetes-related behavioural abnormalities.

1996 - Effect of acute and chronic treatment with triiodothyronine on serotonin levels and serotonergic receptor subtypes in the rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Vergoni, Anna Valeria; Ottani, Alessandra; Bertolini, Alfio
abstract

Hyperthyroidism is often associated with behavioral disorders, and thyroid hormones modify receptor sensitivity as well as the synthesis and/or turnover rate of many neurotransmitters. We evaluated the influence in adult rats of triiodothyronine (T-3), administred s.c. (100 mu g/kg) acutely (once only) or chronically (once a day for 3 or 7 consecutive days), on brain serotonin concentration and on the density and affinity of two brain serotonin (5-HT) receptor subtypes mainly involved in behavioral effects. After both acute and chronic T-3 treatment, serotonin levels increased in the cerebral cortex but not in the hippocampus. The density and affinity of 5-HT1A receptors (using [H-3]-8-OH-DPAT as ligand) were not affected, while there was a significant decrease in the number of 5-HT2 receptors in the cerebral cortex (using [H-3]ketanserin as ligand). This observation might indicate that thyroid hormones enhance 5-HT concentration in certain brain areas, thus causing a down-regulation of 5-HT2 receptors. The serotonergic system could be involved in the complex brain-neurotransmitter imbalance underlying hyperthyroidism-linked behavioral changes.

1996 - Headaches associated with chronic use of analgesics: A therapeutic approach [Articolo su rivista]
Pini, Luigi Alberto; M., Bigarelli; Vitale, Giovanni; Sternieri, Emilio
abstract

We evaluated 102 patients attending the Headache Study Center of the University of Modena who were suffering from chronic daily headache with daily drug intake. Patients underwent either day hospital treatment followed by a standard prophylactic therapy or they started prophylactic therapy immediately. After 30 and 120 days, both the Headache Index and the daily drug intake had significantly improved (P<0.001), and there were no differences in reduction of mean values of the Headache Index or daily drug intake with respect to the two treatments, nor with regard to the prophylactic therapy chosen. Twenty-eight percent of patients reverted to daily drug intake after a 4-month follow-up; these patients took barbiturate-containing mixtures in a higher percentage than other drugs, and within the group of relapsing patients the outpatients relapsed to analgesic intake more than the day hospital-treated patients (P<0.05).

1996 - The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni
abstract

The antinociceptive activity of paracetamol in the hot plate and formalin tests was studied to establish the relationship between antinociceptive activity and the central serotonergic system. Significant antinociceptive activity of paracetarnol was observed in the formalin test at the dose of 300 mg/kg, while, at the dose of 400 mg/kg, the drug was active both in the formalin and in the hot-plate test. Serum paracetamol levels remained sub-toxic and the behavioral profile remained unchanged. Depletion of brain serotonin with p-chlorophenylalanine prevented the antinociceptive effect of paracetamol in the hot-plate test and in the first phase of the formalin response. Paracetamol significantly increased the serotonin content in the pontine and cortical areas (by 75 and 70%, respectively). The pretreatment with p-chlorophenylalanine reduced the 5-hydroxytryptamine (5-HT) content in cortical and pontine areas to 12 and 19% of baseline values, respectively, and prevented the enhancement induced by paracetamol. The maximum number of cortical 5-HT2 receptors was reduced by paracetamol, while the number of 5-HT1A receptors in both cortical and pontine areas was unchanged. Pre-treatment with p-chlorophenylalanine prevented the reduction in the number of 5-HT2 receptors induced by paracetamol. These results provide evidence for the involvement of the central serotonergic system in the antinociceptive effect of paracetamol in the hot plate and formalin tests.

1995 - EFFECTS OF ACETYLSALICYCLIC ACID ON SEROTONIN BRAIN RECEPTOR SUBTYPES [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; M., Dondi; Pini, Luigi Alberto
abstract

1. The lysine salt of acetyl salicylic acid (ASA) at a dose equivalent to 400 mg/kg of acetyl salicylic acid (ASA) was intraperitoneally administered in rats. 2. After 30 and 120 min ASA did not modify the number of receptors nor the affinity of [H-3] 8-OH-DPAT binding sites in pens and cerebral cortex. On the other hand, the receptor number in the cortex membranes decreased significantly using [H-3] ketanserin as ligand, while the receptor number in the pontine membranes did not change. 3. These data support the involvement of central 5-HT receptors in the mode of action of ASA.

1995 - Involvement of brain serotonergic system in the antinociceptive action of acetylsalicylic acid in the rat [Articolo su rivista]
Pini, Luigi Alberto; M., Sandrini; Vitale, Giovanni
abstract

The pain-threshold in the hot-plate test and serotonin (5-HT) receptor binding capacity in the cortex and pontine areas of rat brain were studied after intraperitoneal (ip) administration of acetyl salicylate of lysine equivalent to 400 mg/kg of acetylsalicylic acid (ASA). The antinociceptive activity of ASA was prevented by ip pre-treatment with Parachlorophenylalanine (PCPA) at the rate of 100 mg/kg/day for 4 days. PCPA pre-treatment increased the number of 5-HT receptors and abolished the ASA-induced reduction in 5-HT receptor binding capacity in the cortex but did not affect serum salicylate levels. These results provide support for the hypothesis that the antinociceptive action of ASA, at least in the hot-plate test, involves the central serotonergic system.

1995 - Lack of activity of azapropazone in the hot-plate test and in 5-HT1A and 5-HT2 receptor subtypes in rat brain membranes [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni
abstract

This study aimed to investigate the antinociceptive activity of azapropazone (AZA), a weak prostaglandin synthesis inhibitor using the hot-plate test, and its ability to modify the serotonin-binding capacity in rat brain membranes. it revealed that AZA had no antinociceptive effect in the hot-plate test at the doses of 400 and 600 mg/kg when orally administered (p.o.), and at 400, 500 and 600 mg/kg after intraperitoneal injection (i.p.). At the dose of 600 mg/kg i.p. the drug failed to modify the number and the affinity of 5-HT1A and 5-HT2 receptors in rat brain membranes. in accordance with our previous findings on a positive correlation between NSAIDs antinociception in this experimental model and changes in 5-HT receptor characteristics, these results suggest an association between the lack of AZA-mediated antinociception in the hot-plate test and the drug's inability to modify the characteristics of 5-HT1A and 5-HT2 receptor binding sites in rat brain membranes.

1994 - Drug metabolism in liver cirrhosis: alterations of the time-course of plasma naltrexone levels after oral intake [Abstract in Rivista]
Bertolotti, Marco; Ferrari, Anna; Vitale, Giovanni; Stefani, M; Trenti, T; Loria, Paola; Carulli, N; Sternieri, E.
abstract

In liver cirrhosis significant changes in the serum levels of naltrexone and 6-beta-naltrexolare are observed. These alterations are related to the severity of liver disease

1994 - Lack of activity of Ketorolac in hot-plate test and serotonin binding capacity of brain membranes in rats [Articolo su rivista]
Vitale, Giovanni; Sandrini, Maurizio; Pini, Luigi Alberto
abstract

An increasing number of observations indicate that prostaglandin synthesis inhibition is not a satisfactory explanation for the antinociceptive activity of the non-steroidal anti-inflammatory drugs. In the hot-plate test performed 1 or 2 h after ketorolac at 40, 70 and 100 mg/kg i.p., the drug does not display any significant antinociceptive activity. Nor, at the two higher doses used, does it affect the cortical and pontine serotonin binding capacity of rat brain membranes 2 h after treatment. The data suggest that this lack of antinociceptive activity in the hot-plate test is associated with the drug's inability to affect the central serotoninergic system.

1994 - Naltrexone and 6-Beta-naltrexol concentration/time profile in the treatment of opiate dependence [Abstract in Rivista]
Ferrari, Anna; Bertolotti, Marco; Trenti, T; Vitale, Giovanni; Stefani, M; Sternieri, E.
abstract

The time-course of naltrexone and 6-beta-naltrexol did not change after month of naltrexone treatment in heroin addicts

1994 - Naltrexone: aspetti di farmacologia ed applicazioni cliniche [Articolo su rivista]
Sternieri, E; Ferrari, Anna; Bertolotti, Marco; Stefani, M; Vitale, Giovanni
abstract

L’azione farmacologica del naltrexone consiste in una inibizione competitiva a livello dei siti recettoriali per gli oppiacei, come è stato dimostrato in vitro su organi isolati (Leslie et al., 1979) ed in vivo nell’animale. Il Naltrexone produce l’effetto antagonista spostando le molecole dei morfinici a livello recettoriale e bloccandone l’accesso a livello dei recettori (Martin, 1968; Anou, 1978; Anou, 1982). La somministrazione a lungo termine di naltrexone determina un aumento del numero dei recettori cerebrali di tipo mu, kappa e delta (ma non sigma) (Tempel et al., 1982) ed una ipersensibilità recettoriale nel locus coeruleus che può essere accentuata da un successivo trattamento con morfina (Bardo et al., 1983).. Praticamente il naltrexone non ha attività agonista (Martin et al, 1973; O’Brin et al 1978; Gold et al 1982) e quindi la sospensione del suo uso non si associa a sintomi di astinenza (Anou, 1978), ma in alcuni studi in soggetti sani, non dipendenti da oppiacei, ha determinato un leggero grado di attività agonistica morfinica (miosi, depressione respiratoria, disforia) (Crabtree, 1984; Hollisten et al 1981, Mendelson et al, 1979).

1993 - Disposition of naproxen after oral administration during and between migraine attacks. [Articolo su rivista]
PINI, Luigi Alberto; BERTOLOTTI, Marco; Trenti, T; VITALE, Giovanni
abstract

Naproxen is an anti-inflammatory drug widely used in the management of pain and in the treatment of migraine and headache. As gastrointestinal disturbances are a common feature of migraine, the aim of this study was to evaluate the absorption and the efficacy of naproxen administered during migraine attacks. Ten patients were treated with 500 mg of a soluble form of naproxen during and between migraine attacks. Clinical parameters and drug plasma levels were recorded at scheduled times. Pain reduction, from severe to mild was evident by 6.5 +/- 3.4 hours and the total pain score showed a reduction from 2 hours onwards. Pharmacokinetic data showed a slight delay in drug absorption during attacks (absorption half-life and time of maximum drug concentration were increased during attacks), but overall bioavailability of naproxen, as reflected by area under the curve (AUC) and maximum plasma drug concentration were unchanged. Since pain relief was reported, it may be concluded that delayed absorption has little or no influence on the therapeutic effect of naproxen in migraine attacks in fasting patients.

1993 - Effects of chronic treatment with phenazone on the hot plate test and [3H]-Serotonin binding sites in pons and cortex membranes of the rat [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto; E., Sternieri; Bertolini, Alfio
abstract

Many reports indicate that nonsteroidal anti-inflammatory drugs exert their antinociceptive effect through adrenergic and serotoninergic systems. We investigated the acute and chronic effects of phenazone on the pain threshold and on brain serotonin binding sites. A relationship between phenazone serum levels and the antinociceptive effect was found; acute treatment with phenazone provokes a significant decrease in serotonin binding sites both in the pons and cerebral cortex after 2, 4 and 8 h, but not after 24 h. After 15 and 30 days of treatment, the number of binding sites increases both in the pons and cortex.

1993 - Plasma time-course of naltrexone and 6beta-naltrexol after oral naltrexone administration in patients with liver cirrhosis [Abstract in Atti di Convegno]
Bertolotti, Marco; Ferrari, Anna; Vitale, Giovanni; Trenti, T; Carulli, N; Sternieri, E.
abstract

BACKGROUND/AIMS: Naltrexone has been proposed as a possible treatment of pruritus in cholestasis.These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. METHODS: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis. RESULTS: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

1993 - Plasma time-course of naltrexone and 6beta-naltrexol levels after oral administration in drug addicts and in patients with liver cirrhosis [Abstract in Rivista]
Bertolotti, M; Ferrari, A; Trenti, T; Vitale, G; Macchia, T; Carullin, ; Sternieri, E.
abstract

Abstract sulla cinetica del naltrexone

1993 - Serum levels of naltrexone and 6-beta-naltrexol after oral naltrexone in patients with liver cirrhosis [Abstract in Rivista]
Bertolotti, Marco; Ferrari, Anna; Vitale, Giovanni; Trenti, T; Loria, P; Carulli, N; Sternieri, E.
abstract

liver cirrhosis induces important changes in the time-course of naltrexone with higher bioavailability of naltrexone and slower conversion to 6-beta-naltrexol

1993 - THE ROLE OF SEROTONIN BRAIN RECEPTORS IN THE ANALGESIC EFFECT OF PHENAZONE [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

The effects of treatment with para-chloro-phenyl-alanine (PCPA) (100 mg/kg i.p. for 4 days) were studied on the hot-plate test and on brain 5-HT binding in phenazone treated rats. Phenazone per se induces analgesia in the hot-plate test and decreases the number of cortical and pontine 5-HT binding sites. A pre-treatment with PCPA prevents both the analgesic effect and the reduction of 5-HT binding sites caused by phenazone. These data suggest that the brain serotonin system may play a role in phenazone-induced antinociception.

1992 - BRAIN-SEROTONIN BINDING-CAPACITY, ANALGESIA AND DRUG SERUM LEVELS AFTER ACUTE TREATMENT WITH PHENAZONE IN RATS [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

Phenazone induces analgesia in the hot-plate test and decreases the number of cortical and pontine 5-HT binding sites A pre-treatment with PCPA prevents both the analgesic effect and the reduction of 5-HT binding sites caused by phenazone. These data suggest that the brain serotonin system may play a role in phenazone-induced antinociception.

1992 - PHYSIOLOGICAL-PARAMETERS AND PLASMA-LEVELS AFTER SHORT AND LONG-TERM PROPOFOL INFUSION [Articolo su rivista]
Vitale, Giovanni; Pini, Luigi Alberto; Bertellini, E.
abstract

After IV bolus elimination of propofol is slower than previously reported. After prolonged i.v. infusion of propofol values of elimination half-life ranged widely from 12- to 40 h. , systemic clearance from 1.42 to 1.86 l h-1 and volume of distribution were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the long elimination half-life, blood propofol concentrations appeared to approach steady state within 30 min . This is because this drug displays multicompartment pharmacokinetics, whereas the long elimination half-life of propofol is probably of little significance in designing infusions regimens

1992 - The effect of chronic treatment with phenazone on [3H]-serotonin binding sites in pons and cortex membranes of the rat [Articolo su rivista]
Vitale, Giovanni; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

We studied 36 male rats, 18 o them were trated orally for 30 days with 60 mg/kg/day of phenazone and 18 used as controls. Our data show that a chronic treatment with phenazone increases the number of serotonin receptors in two brain areas while the affinity is not modified; in the same model we demonstrated that phenzone modifies noradrenergic pontine receptors. The role of these changes in receptors characterstics after a long-term treatment with phenazone may contribute to the antinociceptive effect of phenazone.

1991 - Chronic treatment with phenazone modifies pontine noradrenergic receptors in rats. [Capitolo/Saggio]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, M.
abstract

N/A

1991 - Plasma reduced glutathione level and changes in thiol groups after glutathione administration in drug abuser patients - [Articolo su rivista]
T., Trenti; L., Pagliani; Vitale, Giovanni; Pini, Luigi Alberto; B., Botti; V., Vannini; Sternieri, Emilio
abstract

N/A