Publications by authors named "Elena Lucarini"

32 Publications

Efficacy of Extract against Inflammatory Pain: In Vivo Studies in Mice.

Mar Drugs 2021 Jan 21;19(2). Epub 2021 Jan 21.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)-Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini, 6, 50139 Florence, Italy.

(L.) Delile is traditionally used for its beneficial properties. Recently, promising antioxidant and anti-inflammatory biological properties emerged through studying the in vitro activity of the ethanolic leaves extract (POE). The present study aims to investigate the anti-inflammatory and analgesic role of POE in mice. Inflammatory pain was modeled in CD-1 mice by the intraplantar injection of carrageenan, interleukin IL-1β and formalin. Pain threshold was measured by von Frey and paw pressure tests. Nociceptive pain was studied by the hot-plate test. POE (10-100 mg kg) was administered per os. The paw soft tissue of carrageenan-treated animals was analyzed to measure anti-inflammatory and antioxidant effects. POE exerted a dose-dependent, acute anti-inflammatory effect able to counteract carrageenan-induced pain and paw oedema. Similar anti-hyperalgesic and anti-allodynic results were obtained when inflammation was induced by IL-1β. In the formalin test, the pre-treatment with POE significantly reduced the nocifensive behavior. Moreover, POE was able to evoke an analgesic effect in naïve animals. Ex vivo, POE reduced the myeloperoxidase activity as well as TNF-α and IL-1β levels; further antioxidant properties were highlighted as a reduction in NO concentration. POE is the candidate for a new valid strategy against inflammation and pain.
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http://dx.doi.org/10.3390/md19020048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909763PMC
January 2021

Extra virgin olive oil and related by-products (Olea europaea L.) as natural sources of phenolic compounds for abdominal pain relief in gastrointestinal disorders in rats.

Food Funct 2020 Dec 25;11(12):10423-10435. Epub 2020 Nov 25.

Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.

Management of abdominal pain, a common symptom of IBDs and IBS, is still a clinical problem. Extra virgin olive oil (EVOO), a main component of the Mediterranean diet, shows positive effects on chronic inflammation in IBDs. In this study, the effect of the oral administration of EVOO (3 mL) and two olive milling by-products, DPA (300 mg kg) and DRF (300 mg kg), on preventing the development of abdominal pain in a DNBS-induced colitis model in rats was evaluated. The doses were chosen with the aim of simulating a plausible daily intake in humans. DPA and EVOO treatments significantly reduced the abdominal viscero-motor response to colon-rectal distension at 2 and 3 mL of balloon distension volume, both 7 and 14 days after the DNBS-injection. DRF showed efficacy in the reduction of visceral hypersensitivity only with 3 mL balloon inflation. In awake animals, DPA and DRF reduced pain perception (evaluated as abdominal withdrawal reflex) with all balloon distension volumes, while EVOO was effective only with higher distension volumes. Fourteen days after the DNBS-injection, all samples reduced the macroscopic intestinal damage (quantified as the macroscopic damage score) also showing, at the microscopic level, a reduction of the inflammatory infiltrate (quantified by hematoxylin and eosin analysis), fibrosis (highlighted by picrosirius red staining), the increase in mast cells and their degranulation (analyzed by triptase immunohistochemistry). This is the first report on the promotion of abdominal pain relief in a rat model obtained administering EVOO and two derived by-products. Our results suggest a protective role of phenol-rich EVOO and milling by-products, which may be proposed as food ingredients for novel functional foods.
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http://dx.doi.org/10.1039/d0fo02293dDOI Listing
December 2020

()-3-Furan-2-yl---tolyl-acrylamide and its Derivative DM489 Decrease Neuropathic Pain in Mice Predominantly by α7 Nicotinic Acetylcholine Receptor Potentiation.

ACS Chem Neurosci 2020 11 19;11(21):3603-3614. Epub 2020 Oct 19.

Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia.

The main objective of this study was to determine whether ()-3-furan-2-yl---tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at α7 and α9α10 nicotinic acetylcholine receptors (nAChRs) and Ca2.2 channels expressed alone or coexpressed with G protein-coupled GABA receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemotherapy-induced neuropathic pain is decreased by PAM-2 (3 mg/kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the α7-selective antagonist methyllycaconitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) α7 nAChRs with 2-7 times higher potency than that for hCa2.2 channel inhibition and an even greater difference compared to that for rα9α10 nAChR inhibition. These results support the notion that α7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.
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http://dx.doi.org/10.1021/acschemneuro.0c00476DOI Listing
November 2020

Intranasal Low-Dose Naltrexone Against Opioid Side Effects: A Preclinical Study.

Front Pharmacol 2020 18;11:576624. Epub 2020 Sep 18.

Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the clinical practice. Unfortunately, together with analgesia, a number of adverse effects can occur such as nausea, vomiting, constipation, gastrointestinal alterations and cognitive impairments. Naltrexone is a competitive antagonist of opioid receptors commonly used to treat opioid addiction; its oral use against agonists side effects is limited by the decrease of opioids-therapeutic efficacy and own adverse effects. The intranasal delivery of naltrexone could offer a quick and effective achievement of CNS based on extracellular mechanisms including perineural and perivascular transport. The aim of the study was to test the efficacy of intranasal low-dose naltrexone in reducing intraperitoneal morphine and oxycodone side effects in rodents. In mice, 1 μg naltrexone intranasally administered 30 min before opioids reduced cognitive impairments and motor alteration induced by 10 mg kg morphine and 60 mg kg oxycodone in the Passive avoidance and Rota rod tests, respectively. Moreover, naltrexone rebalanced opioid-induced reduction of the intestinal transit and latency of feces expulsion as well as food intake inhibition. Importantly, 1 μg naltrexone instillation did not block analgesia as demonstrated by the Hot plate test. In rats, intranasal naltrexone counteracted the opioid-induced pica phenomenon related to emesis and increased water and palatable food intake. The effects were comparable to that achieved by metoclopramide used as reference drug. Treatments did not influence body weight. Lastly, the safety of the intranasal delivery has been checked by hematoxylin-eosin staining that did not show histological alterations of the nasal cavity. In conclusion, intranasal low-dose naltrexone counteracted morphine and oxycodone induced gastrointestinal and CNS side effects without impairing opioid analgesia. It is a candidate to be a valid clinical strategy deserving deep analysis.
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http://dx.doi.org/10.3389/fphar.2020.576624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531600PMC
September 2020

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients.

Microbiome 2020 10 1;8(1):140. Epub 2020 Oct 1.

Dept. of Experimental and Clinical Medicine, University of Florence, 50134, Florence, Italy.

Background: The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions.

Results: Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected.

Conclusion: These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00914-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532115PMC
October 2020

The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis.

Eur J Med Chem 2020 Dec 29;208:112858. Epub 2020 Sep 29.

Department of Pharmacy, University of Pisa, 56126, Pisa, Italy. Electronic address:

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system that eventually leads to progressive neurodegeneration and disability. Recent findings highlighted the emerging role of each target of the endocannabinoid system in controlling the symptoms and disease progression of multiple sclerosis. Therefore, multi-target modulators of the endocannabinoid system could provide a more effective pharmacological strategy as compared to the single target modulation. In this work, N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide (B2) was identified as the most promising compound with dual agonism at cannabinoid receptors type-1 and cannabinoid receptors type-2 and good drug-like properties. In in vitro assays, B2 reduced glutamate release from rat synaptosomes through interaction with cannabinoid receptors type-1 and modulated the production of the pro- and anti-inflammatory cytokines (interleukins IL-1β and IL-6 and interleukin IL-10 respectively) via cannabinoid receptors type-2 activation. Furthermore, B2 demonstrated antinociceptive effects in an animal model of neuropathic pain and efficacy in an experimental autoimmune encephalomyelitis model of multiple sclerosis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112858DOI Listing
December 2020

Toxicological Profile of the Pain-Relieving Antioxidant Compound Thioctic Acid in Its Racemic and Enantiomeric Forms.

Antioxidants (Basel) 2020 Aug 14;9(8). Epub 2020 Aug 14.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)-Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini, 6, 50139 Florence, Italy.

Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (-). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer compared to the levorotatory compound, we recently preclinically and clinically showed that (+) thioctic acid is a pain-reliever as effective as double-dosed racemate. We investigated acute and subchronical toxicity of (+/-) thioctic acid, (-) thioctic acid, (+) thioctic acid and (+) salt thioctic acid on Sprague-Dawley rats. For acute toxicity, compounds were administered intraperitoneally (i.p.) with a single-injection at 125, 240, 360, 480 µmol/kg, then rodents were tested for motorial coordination and minimum lethal dose (LDmin). A subtoxic dose (360 µmol/kg) was administered i.p. for 15 days and we finally evaluated motorial impairment, glycemia, organ toxicity, and apoptosis state. Acutely administered, the highest doses of all thioctic acid compounds negatively affected motorial ability and (-) thioctic acid LDmin resulted higher than the others. Subchronic administrations caused overall body weight loss, motorial impairment, mass loss in some organs. (+/-) and (-) thioctic acid injections enhanced caspase-3 activity in some organs, (-) enantiomer-treated animals displayed more marked organ toxicity signs. Together with our previous study on the biologic role of enantiomers, these data suggest a therapeutic use of (+) enantiomer-based formulations, thus lowering dose and toxicity without affecting the positive effects brought by the drug.
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http://dx.doi.org/10.3390/antiox9080749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464875PMC
August 2020

Deepening the Mechanisms of Visceral Pain Persistence: An Evaluation of the Gut-Spinal Cord Relationship.

Cells 2020 07 24;9(8). Epub 2020 Jul 24.

Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the , transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.
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http://dx.doi.org/10.3390/cells9081772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464824PMC
July 2020

The Anti-Inflammatory and Pain-Relieving Effects of AR170, an Adenosine A Receptor Agonist, in a Rat Model of Colitis.

Cells 2020 06 21;9(6). Epub 2020 Jun 21.

School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, 62032 Camerino (MC), Italy.

The pharmacological activation of A receptors has shown potential usefulness in the management of bowel inflammation. However, the role of these receptors in the control of visceral hypersensitivity in the presence of intestinal inflammation has not been investigated. The effects of AR170, a potent and selective A receptor agonist, and dexamethasone (DEX) were tested in rats with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis to assess their tissue inflammatory parameters. The animals received AR170, DEX, or a vehicle intraperitoneally for 6 days, starting 1 day before the induction of colitis. Visceral pain was assessed by recording the abdominal responses to colorectal distension in animals with colitis. Colitis was associated with a decrease in body weight and an increase in spleen weight. The macroscopic damage score and tissue tumor necrosis factor (TNF), interleukin 1β (IL-1β), and myeloperoxidase (MPO) levels were also enhanced. AR170, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight, ameliorated macroscopic colonic damage, and decreased TNF, IL-1β, and MPO tissue levels. The enhanced visceromotor response (VMR) in rats with colitis was decreased via AR170 administration. In rats with colitis, AR170 counteracted colonic inflammatory cell infiltration and decreased pro-inflammatory cytokine levels, thereby relieving visceral hypersensitivity.
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http://dx.doi.org/10.3390/cells9061509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348903PMC
June 2020

Pomegranate Mesocarp against Colitis-Induced Visceral Pain in Rats: Effects of a Decoction and Its Fractions.

Int J Mol Sci 2020 Jun 17;21(12). Epub 2020 Jun 17.

Department of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

The management of chronic visceral pain related to Inflammatory Bowel Diseases or Irritable Bowel Syndrome is still a clinical problem and new therapeutic strategies continue to be investigated. In the present study, the efficacy of a pomegranate decoction and of its polysaccharide and ellagitannin components in preventing the development of colitis-induced abdominal pain in rats was evaluated. After colitis induction by 2,4-dinitrobenzenesulfonic acid (DNBS), the pomegranate decoction (300 mg kg), polysaccharides (300 mg kg), and ellagitannins (45 mg kg) were orally administered for 14 days. Repeated treatment with decoction reduced visceral hypersensitivity in the colitic animals both at 7 and 14 days. Similar efficacy was shown by polysaccharides, but with lower potency. Ellagitannins administered at dose equivalent to decoction content showed higher efficacy in reducing the development of visceral pain. Macroscopic and microscopic evaluations performed on the colon 14 days after the damage showed that all three preparations reduced the overall amount of mast cells, the number of degranulated mast cells, and the density of collagen fibers in the mucosal stroma. Although ellagitannins seem to be responsible for most of the beneficial effects of pomegranate on DNBS-induced colitis, the polysaccharides support and enhance its effect. Therefore, pomegranate mesocarp preparations could represent a complementary approach to conventional therapies for promoting abdominal pain relief.
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http://dx.doi.org/10.3390/ijms21124304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353021PMC
June 2020

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels.

Pain 2020 09;161(9):2179-2190

Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Division of Pharmacology and Toxicology, Florence, Italy.

Abstract: Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently, their activity has been related to the block of N-type voltage-gated Ca2+ channels (Cav2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A3AR agonists in reducing postinflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intracolonic instillation of 2,4-dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 mL 50% EtOH). Visceral hypersensitivity was assessed by measuring the visceromotor response and the abdominal withdrawal reflex to colorectal distension. The effects of A3AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Cav2.2 blocker PD173212, and the clinically used drug linaclotide. A3AR agonists significantly reduced DNBS-evoked visceral pain both in the postinflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Cav2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A3AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A3AR agonists inhibited Cav2.2 in dorsal root ganglia neurons isolated from either control or DNBS-treated rats. The effect on Ca2+ current was PD173212-sensitive and prevented by MRS1523. A3AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.
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http://dx.doi.org/10.1097/j.pain.0000000000001905DOI Listing
September 2020

Effects of the Combination of β-Hydroxy-β-Methyl Butyrate and R(+) Lipoic Acid in a Cellular Model of Sarcopenia.

Molecules 2020 04 30;25(9). Epub 2020 Apr 30.

Department of Neurosciences, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

Sarcopenia is a clinical problem associated with several pathological and non-pathological conditions. The aim of the present research is the evaluation of the pharmacological profile of the leucine metabolite β-hydroxy-β-methyl butyrate (HMB) associated with the natural R(+) stereoisomer of lipoic acid (R(+)LA) in a cellular model of muscle wasting. The C2C12 cell line is used as myoblasts or is differentiated in myotubes, sarcopenia is induced by dexamethasone (DEX). A Bonferroni significant difference procedure is used for a post hoc comparison. DEX toxicity (0.01-300 µM concentration range) is evaluated in myoblasts to measure cell viability and caspase 3 activation after 24 h and 48 h; cell incubation with 1 µM DEX for 48 h is chosen as optimal treatment for decreasing cell viability and increasing caspase 3 activity. R(+)LA or HMB significantly prevents DEX-induced cell mortality; the efficacy is improved when 100 µM R(+)LA is combined with 1 mM HMB. Regarding myoblasts, this combination significantly reduces DEX-evoked O production and protein oxidative damage. During the early phase of myotube formation, the mixture preserves the number of myogenin-positive cells, whereas it completely prevents the DEX-dependent damage in a later phase of myotube differentiation (7 days), as evaluated by cell diameter and percentage of multinucleated cells. R(+)LA in association with HMB is suggested for sarcopenia therapy.
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http://dx.doi.org/10.3390/molecules25092117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249096PMC
April 2020

Researching New Therapeutic Approaches for Abdominal Visceral Pain Treatment: Preclinical Effects of an Assembled System of Molecules of Vegetal Origin.

Nutrients 2019 Dec 20;12(1). Epub 2019 Dec 20.

Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.

Abdominal pain is a frequent symptom of irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBDs). Although the knowledge of these pathologies is progressing, new therapeutic strategies continue to be investigated. In the present study, the effect of a system of molecules of natural origin (a medical device according to EU Directive 93/42/EC, engineered starting from resins, polysaccharides and and polyphenols) was evaluated against the intestinal damage and visceral pain development in DNBS-induced colitis model in rats. The system (250 and 500 mg kg) was orally administered once daily, starting three days before the injection of 2,4-dinitrobenzenesulfonic acid (DNBS) and for 14 days thereafter. The viscero-motor response (VMR) to colon-rectal balloon distension (CRD) was used as measure of visceral sensitivity. The product significantly reduced the VMR of DNBS-treated animals. Its effect on pain threshold was better than dexamethasone and mesalazine, and not lower than amitriptyline and otilonium bromide. At microscopic and macroscopic level, the tested system was more effective in protecting the intestinal mucosa than dexamethasone and mesalazine, promoting the healing of tissue lesions. Therefore, we suggest that the described system of molecules of natural origin may represent a therapeutic option to manage painful bowel diseases.
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http://dx.doi.org/10.3390/nu12010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019336PMC
December 2019

Antioxidant-Conjugated 1,2,4-Triazolo[4,3-]pyrazin-3-one Derivatives: Highly Potent and Selective Human A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain.

J Med Chem 2019 09 10;62(18):8511-8531. Epub 2019 Sep 10.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy.

New 8-amino-6-aryl-1,2,4-triazolo[4,3-]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines () were potent and selective hA AR antagonists ( = 0.17-54.5 nM). Compounds , , and , featuring antioxidant moieties, and compound , lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative and the (4-hydroxy-3,5-di--butyl)benzoyl-analogue which were effective in reducing the oxygen free radical level. The lipoyl-derivative was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of makes it a promising neuroprotective agent in oxidative stress-related diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00778DOI Listing
September 2019

Meal against Diabetic Neuropathic Pain: An HS-Mediated Effect of Glucoerucin.

Molecules 2019 08 19;24(16). Epub 2019 Aug 19.

Department of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy.

The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed meal, along with its main glucosinolate, glucoerucin (GER), on diabetic neuropathic pain induced in mice by streptozotocin (STZ). The mechanism of action was also investigated. Hypersensitivity was assessed by paw pressure and cold plate tests after the acute administration of the compounds. Once bio-activated by myrosinase, both E. sativa defatted meal (1 g kg p.o.) and GER (100 µmol kg p.o., equimolar to meal content) showed a dose-dependent pain-relieving effect in STZ-diabetic mice, but the meal was more effective than the glucosinolate. The co-administration with HS scavengers abolished the pain relief mediated by both meal and GER. Their effect was also prevented by selectively blocking Kv7 potassium channels. Repeated treatments with E. sativa meal did not induce tolerance to the anti-hypersensitive effect. In conclusion, meal can be suggested as a new nutraceutical tool for pain relief in patients with diabetic neuropathy.
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http://dx.doi.org/10.3390/molecules24163006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721019PMC
August 2019

Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold.

Bioorg Med Chem 2019 10 9;27(19):115045. Epub 2019 Aug 9.

Dipartimento di Biotecnologie, Chimica e Farmacia, (Dipartimento d'Eccellenza 2018-2022), Università di Siena, Via A. Moro, I-53100 Siena, Italy. Electronic address:

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.
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http://dx.doi.org/10.1016/j.bmc.2019.115045DOI Listing
October 2019

L. Extract: Alpha-Amylase Inhibition against Metabolic Syndrome in Mice.

Nutrients 2019 08 1;11(8). Epub 2019 Aug 1.

Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy.

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans ( L) was tested against the hallmarks of metabolic syndrome. The efficacy of a repeated treatment with extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome.
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http://dx.doi.org/10.3390/nu11081778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723332PMC
August 2019

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity.

J Med Chem 2019 08 26;62(15):6894-6912. Epub 2019 Jul 26.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy.

A new series of amino-3,5-dicyanopyridines () was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) AAR affinity and an inverse agonist profile. While most of the compounds are hAAR-selective, some derivatives behave as mixed hAAR inverse agonists/A and A AR antagonists. The latter compounds ( showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available structure-activity relationships.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00106DOI Listing
August 2019

Effect of NIR laser therapy by MLS-MiS source against neuropathic pain in rats: in vivo and ex vivo analysis.

Sci Rep 2019 06 26;9(1):9297. Epub 2019 Jun 26.

Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.

Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma.
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http://dx.doi.org/10.1038/s41598-019-45469-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594937PMC
June 2019

N-aryl-N'-ureido-O-sulfamates: Potent and selective inhibitors of the human Carbonic Anhydrase VII isoform with neuropathic pain relieving properties.

Bioorg Chem 2019 08 6;89:103033. Epub 2019 Jun 6.

University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address:

Herein we report for the first time an efficient synthetic procedure for the preparation of N-aryl-N'-ureido-O-sulfamates (AUSs) as a new class of Carbonic Anhydrase Inhibitors (CAIs). The compounds were tested for the inhibition of several human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms. Interesting inhibition activity and high selectivity against CA VII and XII versus CA I and II, with Ks in the low nanomolar range, were observed. Molecular modeling studies allowed us to decipher the structural features underpinning the selective inhibitory profile of AUSs towards isoforms CAs VII and XII. A selection of sulfamates showed promising neuropathic pain modulating effects in an in vivo animal model of oxaliplatin induced pain.
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http://dx.doi.org/10.1016/j.bioorg.2019.103033DOI Listing
August 2019

Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons.

Pain 2019 05;160(5):1103-1118

Division of Pharmacology and Toxicology, Department of NEUROFARBA, University of Florence, Italy.

Recently, studies have focused on the antihyperalgesic activity of the A3 adenosine receptor (A3AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A3AR on the excitability of small- to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3- to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A3AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A3AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca-activated K (KCa) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca influx via N-type voltage-dependent Ca channels, as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca currents, and its effect was inhibited by 56% in the presence of A3AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A3AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca measurements confirmed the inhibitory role of A3AR on DRG neuronal firing. We conclude that pain-relieving effects observed on A3AR activation could be mediated through N-type Ca channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A3AR-based therapy as a viable approach to alleviate pain in different pathologies.
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http://dx.doi.org/10.1097/j.pain.0000000000001488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669900PMC
May 2019

Pain Relieving Effect of-NSAIDs-CAIs Hybrid Molecules: Systemic and Intra-Articular Treatments against Rheumatoid Arthritis.

Int J Mol Sci 2019 Apr 18;20(8). Epub 2019 Apr 18.

Department of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy.

To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg) or single i.a injection (1 mg ml, 50 µL) with NSAIDs-CAIs hybrid molecules, named and , was evaluated. The molecules and , which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, and were formulated in liposomes (lipo and lipo , both 1 mg ml) and directly administered by a single i.a. injection seven days after CFA injection. Lipo decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.
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http://dx.doi.org/10.3390/ijms20081923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514875PMC
April 2019

Intra-articular mucilages: behavioural and histological evaluations for a new model of articular pain.

J Pharm Pharmacol 2019 Jun 19;71(6):971-981. Epub 2019 Feb 19.

NEUROFARBA - Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.

Objectives: The creation of a new valid preclinical model of articular pain by the intra-articular (i.a.) injection of mucilages for the screening of new treatments against arthritis.

Methods: A single intra-articular injection (20 μl) of mucilages (from Althaea officinalis roots and Linum usitatissimun seeds) or vegetal components (Amorphophallus konjac gum powder and β-glucan, used as reference standard) were assessed in the rat. The pathology progression was monitored by behavioural measurements (paw pressure test, von Frey test, incapacitance test and beam balance test) and compared to that induced by the i.a. injections of monoiodioacetate (MIA) and Complete Freund's Adjuvant (CFA), well-recognized models of osteoarthritis and rheumatoid arthritis, respectively.

Key Findings: Among all, the mucilage of L. usitatissimun showed the best pro-algic profile inducing a painful long-lasting condition. Hypersensitivity was characterized as a mixed form of inflammatory and neuropathic pain by the responsiveness to ibuprofen (100 mg/kg, p.o.) and pregabalin (30 mg/kg, p.o.). The histological evaluation of joint showed a damage that represents both MIA and CFA features.

Conclusions: In conclusion, a single i.a. injection of L. usitatissimun mucilage can represent a valid model to assess articular pain in the rat for the screening of new treatments against arthritis.
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http://dx.doi.org/10.1111/jphp.13078DOI Listing
June 2019

Efficacy of isothiocyanate-based compounds on different forms of persistent pain.

J Pain Res 2018 19;11:2905-2913. Epub 2018 Nov 19.

Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research, and Child Health (Neurofarba), University of Florence, Florence, Italy,

Purpose: Current pharmacotherapy for persistent pain related to neuropathy or articular diseases is unsatisfactory, due to the large number of unresponsive patients and side effects. Isothiocyanates (ITCs) are a class of natural or synthetic compounds characterized by the general formula R-NCS. ITCs show antihyperalgesic effects in models of central and peripheral nervous tissue injury and anti-inflammatory properties. The pharmacodynamics are strictly related to the release of the gasotransmitter hydrogen sulfide (HS) from their moiety. In particular, phenyl ITC (PITC) and 3-carboxyphenyl ITC (3C-PITC) exhibit interesting slow HS-release properties suitable for treating painful pathology. The aim of the present work was to evaluate the efficacy of PITC and 3C-PITC against mechanical hyperalgesia and spontaneous pain induced by nerve injury and osteoarthritis.

Methods: Nerve injury and osteoarthritis were induced in rats by ligation of the sciatic nerve (chronic constriction injury) and intra-articular injection of monoiodoacetate, respectively. Behavioral tests were performed 14 days after damage induction.

Results: Single subcutaneous administrations of PITC, 3C-PITC (4.43 and 13.31 µmol kg, respectively) were able to completely reverse hypersensitivity to noxious stimuli in both models of neuropathic and osteoarticular pain. The effect of ITCs was compared with that of NaHS, the prototypical HS donor, showing similar efficacy and higher potency. ITCs and NaHS also reduced spontaneous pain.

Conclusion: ITCs offer a promising novel approach to counteract persistent, drug-resistant painful pathology.
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http://dx.doi.org/10.2147/JPR.S161882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250104PMC
November 2018

Effect of glucoraphanin and sulforaphane against chemotherapy-induced neuropathic pain: Kv7 potassium channels modulation by H S release in vivo.

Phytother Res 2018 Nov 2;32(11):2226-2234. Epub 2018 Aug 2.

Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.

The beneficial effects of isothiocyanate-based compounds, as well as their safety, have been shown in neuropathological disorders, such as neuropathic pain. Aim of the present work was to study the efficacy of the glucosinolate glucoraphanin (GRA) and the derived isothiocyanate sulforaphane (SFN), secondary metabolites occurring exclusively in Brassicales, on chemotherapy-induced neuropathic pain. Mice were repeatedly treated with oxaliplatin (2.4 mg kg ip) for 14 days to induce neuropathic pain. GRA and SFN effects were evaluated after a single administration on Day 15 or after a daily repeated oral and subcutaneous treatment starting from the first day of oxaliplatin injection until the 14 day. Single subcutaneous and oral administrations of GRA (4.43-119.79 μmol kg ) or SFN (1.33-13.31 μmol kg ) reduced neuropathic pain in a dose-dependent manner. The repeated administration of GRA and SFN (respectively 13.31 and 4.43 μmol kg ) prevented the chemotherapy-induced neuropathy. The co-administration of GRA and SFN in mixture with the H S binding molecule, haemoglobin, abolished their pain-relieving effect, which was also reverted by pretreating the animals with the selective blocker of Kv7 potassium channels, XE991. GRA and SFN reduce neuropathic pain by releasing H S and modulating Kv7 channels and show a protective effect on the chemotherapy-induced neuropathy.
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http://dx.doi.org/10.1002/ptr.6159DOI Listing
November 2018

Identification of the First Synthetic Allosteric Modulator of the CB Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief.

J Med Chem 2019 01 23;62(1):276-287. Epub 2018 Jul 23.

Department of Pharmacy , University of Pisa , 56126 Pisa , Italy.

The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands. Here we identify the first ever synthesized positive allosteric modulator (PAM) that targets CBRs. The evidence for this was obtained using [H]CP55940 and [S]GTPγS binding assays. This finding will be useful for the characterization of allosteric binding site(s) on CBRs which will be essential for the further development of CBR allosteric modulators. Moreover, the new CBR PAM displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain, raising the possibility that it might be a good candidate for clinical development.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00368DOI Listing
January 2019

Ultramicronized -Palmitoylethanolamine Supplementation for Long-Lasting, Low-Dosed Morphine Antinociception.

Front Pharmacol 2018 1;9:473. Epub 2018 Jun 1.

Department of Neuroscience, Psychology, Drug Research and Child Health-Neurofarba-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.

The facilitation of opioid medication is eliciting a nemetic problem since increasing overdose deaths involve prescription of opioid pain relievers. Chronic painful diseases require higher doses of opioids, progressively with the development of tolerance to the antinociceptive effect. Novel strategies for the maintenance of low dosed opioid effectiveness are necessary to relieve pain and decrease abuse, overdose, and side effects. -Palmitoylethanolamine (PEA) is an endogenous compound able to preserve the homeostasis of the nervous system and to delay the development of morphine tolerance. In the present study, a preemptive and continuative treatment with PEA (30 mg/kg, daily, ) enhanced the acute antinociceptive efficacy of morphine (10 mg/kg subcutaneously) in rats and prolonged the responsiveness to the natural opioid. Moreover, PEA-treated animals had a more rapid recovery from tolerance. Four opioid free days were enough to regain sensitivity to morphine whereas control animals needed 31 days for full recovery of tolerance. Characteristically, PEA acquired antinociceptive properties in tolerant animals, suggesting the possibility of an integrated morphine/PEA treatment protocol. To maintain a significant analgesia, morphine dose had to be increased from 5 up to 100 mg/kg over 17 days of daily treatment. The same pain threshold increase was achieved in animals using preemptive PEA (30 mg/kg, daily) joined to a combinatorial acute treatment with morphine (5-20 mg/kg s.c.) and PEA (30-120 mg/kg, p.o.). Representatively, on day 17, the magnitude of analgesia induced by 100 mg/kg morphine was obtained by combining 13 mg/kg of morphine with 120 mg/kg of PEA. PEA strengthens the efficacy and potency of morphine analgesia, allowing prolonged and effective pain relief with low doses. PEA is suggested in association with morphine for chronic pain therapies distinguished by low risk of side effects.
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http://dx.doi.org/10.3389/fphar.2018.00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992817PMC
June 2018

Design, synthesis and X-ray crystallography of selenides bearing benzenesulfonamide moiety with neuropathic pain modulating effects.

Eur J Med Chem 2018 Jun 19;154:210-219. Epub 2018 May 19.

Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. Electronic address:

A series of selenides bearing benzensulfonamide were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Potent inhibitory action, in the low nanomolar range, was detected against isoforms hCA II and VII, which are known to be involved in neuropathic pain modulation. These selenides showed on the other hand moderate inhibition against the cytosolic isoforms hCA I and transmembrane hCA IX. X-ray crystallographic data of two derivatives bound to hCA II allowed us to rationalize the excellent inhibitory data. In a mice model of neuropathic pain induced by oxaliplatin, some of the strong CA II/VII inhibitors induced a long lasting pain relieving effect.
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http://dx.doi.org/10.1016/j.ejmech.2018.05.026DOI Listing
June 2018

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

Eur J Pharmacol 2018 Mar 31;823:79-86. Epub 2018 Jan 31.

Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Florence, Italy. Electronic address:

The development of tolerance to the antinociceptive effect is a main problem associated with the repeated administration of opioids. The progressively higher doses required to relieve pain reduce safety and exacerbate the side effects of classical opioid receptor agonists like morphine. Nociceptin/orphanin FQ (N/OFQ) and its NOP receptor constitute the fourth endogenous opioid system that is involved in the control of broad spectrum of biological functions, including pain transmission. Aim of this work was to evaluate the relevance of the N/OFQ-NOP system in morphine antinociceptive action and in the development of morphine tolerance in the rat. Continuous spinal intrathecal infusion of morphine (1-3 nmol/h) evoked analgesic effects for 5 days in wild type animals. The same doses infused in NOP(-/-) rats showed a lower analgesic efficacy, while the onset of tolerance was delayed to day 9. N/OFQ (1-3 nmol/h), continuously infused in NOP(+/+) animals, showed an analgesic profile similar to morphine. Immunohistochemical analysis of the dorsal horn of the spinal cord of morphine tolerant NOP(+/+) rats showed an increased number of Iba1- and GFAP-positive cells (microglia and astrocytes, respectively). Interestingly, microglia but not astrocyte activation was observed in NOP(-/-) morphine tolerant rat. A selective activation of astrocytes was observed in the dorsal horn of wild type N/OFQ tolerant rats. The antinociceptive effect of morphine partially depends by the N/OFQ-NOP system that participates in the development of morphine tolerance. In particular, NOP receptors are involved in morphine-induced astrocyte activation, and N/OFQ per se increases astrocyte density.
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http://dx.doi.org/10.1016/j.ejphar.2018.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064644PMC
March 2018

Photobiomodulation therapy by NIR laser in persistent pain: an analytical study in the rat.

Lasers Med Sci 2017 Nov 28;32(8):1835-1846. Epub 2017 Jul 28.

ASA Campus Joint Laboratory, ASA Res. Division-Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

Over the past three decades, physicians have used laser sources for the management of different pain conditions obtaining controversial results that call for further investigations. In order to evaluate the pain relieving possibilities of photobiomodulation therapy (PBMT), we tested two near infrared (NIR) laser systems, with different power, against various kinds of persistent hyperalgesia animal models. In rats, articular pain was reproduced by the intra-articular injection of sodium monoiodoacetate (MIA) and complete Freund's adjuvant (CFA), while compressive neuropathy was modelled by the chronic constriction injury of the sciatic nerve (CCI). In MIA and CFA models, (NIR) laser (MLS-Mphi, ASA S.r.l., Vicenza, Italy) application was started 14 days after injury and was performed once a day for a total of 13 applications. In MIA-treated animals, the anti-hyperalgesic effect of laser began 5 min after treatment and vanished after 60 min. The subsequent applications evoked similar effects. In CFA-treated rats, laser efficacy started 5 min after treatment and disappeared after 180 min. In rats that underwent CCI, two treatment protocols with similar fluence but different power output were tested using a new experimental device called Multiwave Locked System laser (MLS-HPP). Treatments began 7 days after injury and were performed during 3 weeks for a total of 10 applications. Both protocols reduced mechanical hyperalgesia and hindlimb weight bearing alterations until 60 min after treatment with a higher efficacy recorded for the animals treated using the higher power output. In conclusion, this study supports laser therapy as a potential treatment for immediate relief of chronic articular or neuropathic pain.
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http://dx.doi.org/10.1007/s10103-017-2284-9DOI Listing
November 2017