Livio Luongo

Università degli Studi della Campania "Luigi Vanvitelli · Dipartimento di Medicina Sperimentale

Following insults or injury, microglia cells are activated contributing to the cytotoxic response or by promoting an immune-mediated damage resolution. Microglia cells express HCA2R, a hydroxy carboxylic acid (HCA) receptor, which has been shown to mediate neuroprotective and anti-inflammatory effects. In this study we found that HCAR2 expression l...

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn partic...

Neuroinflammation is an emerging therapeutic target in chronic degenerative and autoimmune diseases, such as osteoarthritis (OA) and rheumatoid arthritis. Mast cells (MCs) play a key role in the homeostasis of joints and the activation of MCs induces the release of a huge number of mediators, which fuel the fire of neuroinflammation. Particularly,...

Background: Unplanned hospital readmissions (HRAs) are very common in cancer patients. These events can potentially impair the patients' health-related quality of life and increase cancer care costs. In this study, data-driven prediction models were developed for identifying patients at a higher risk for HRA. Methods: A large dataset on cancer p...

Up to 80 % nursing home residents with dementia experiences chronic pain. Contextually, 97 % presents fluctuant neuropsychiatric symptoms (NPS). Among the most challenging is agitation, connected with undertreated pain and managed through neuroleptics doubling death risk. Evidence is accumulating in favor of the involvement of the endocannabinoid s...

Melatonin, through its G protein‐coupled MT2 receptor, is implicated in analgesia, but the relationship between MT2 receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured, SNI), the selective melatonin MT2 agonist UCM924 reversed the allodynia (a pain response to a non‐noxious stimulus), and thi...

Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic d...

Cinnabarinic acid (CA) is a trace kynurenine metabolite, which activates both type-4 metabotropic glutamate (mGlu4) and arylic hydrocarbon (Ah) receptors. We examined the action of CA in models of inflammatory and neuropathic pain moving from the evidence that mGlu4 receptors are involved in the regulation of pain thresholds. Systemic administratio...

Objectives: The Cannabinoid Receptor type 2 (CB2) is involved in inflammation and immune cell modulation. In previous studies, we demonstrated the association between the CNR2 rs35761398 polymorphism and the risk for pediatric inflammatory bowel disease (IBD). In this study, we analyzed the intestinal biopsies from Crohn disease (CD) and ulcerativ...

Chronic social isolation generates a persistent state of stress associated with obesity along with some neuro-endocrine disorders and central behavioral sequelae (eg anxiety, depression, aggression, and allodynia). In this study, we evaluated the effect of social isolation on body weight, depressive- and anxious-aggressive-like behavior, as well as...

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and lute...

Following injury, the endocannabinoid system is activated in the brain suggesting a strategic role in the self-repair mechanisms. Indeed endocannabinoid system manipulation ameliorates traumatic brain injury (TBI) symptoms. Cannabidiol (CBD), together with △⁹-tetrahydrocannabinol (THC), is the main phytocannabinoid extracted from the plant Cannabis...

Neuropathic pain has long-term consequences in terms of affective and cognitive disturbances suggesting the involvement of supraspinal mechanisms. In the present study, we used the spared nerve injury (SNI) model to characterize the development of sensory and aversive components of neuropathic pain, and to determine their electrophysiological impac...

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target...

An amendment to this paper has been published and can be accessed via the original article.

Purpose: The aim of the present work was to evaluate the knowledge and prescriptive habits of clinicians involved in the management of chronic non cancer pain (CNCP), with a special focus on the use of opioids. Methods: A Delphi method was used. A Board of specialists elaborated and discussed a series of statements, based on available literature...

Aims: This study assessed the use of MALDI-TOF mass spectrometry as an alternative method to identify species associated with the thanatomicrobiota and epinecrotic communities. Methods and results: The study was conducted on 10 murine cadavers, and microbiological swabs were collected from five external anatomical sites (eyes, ears, nose, mouth,...

The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test a...

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, t...

Background The endocannabinoid (EC) system has been recently indicated as a possible therapeutic target in inflammatory bowel disease patients (IBD). G-protein-coupled cannabinoid receptors type 1 and 2 (CB1 and CB2) are the two most important components of the EC system. In our previous study, we demonstrated that a specific CB2 variant contribute...

The bioactive form of vitamin D, 1,25-dihydroxyvitamin D (1,25D3), exerts immunomodulatory actions resulting in neuroprotective effects potentially useful against neurodegenerative and autoimmune diseases. In fact, vitamin D deficiency status has been correlated with painful manifestations associated with different pathological conditions. In this...

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synth...

The two most important and studied phytocannabinoids present in Cannabis sativa L. are undoubtedly cannabidiol (CBD), a non-psychotropic compound, but with other pharmacological properties, and Δ 9-tetrahydrocannabinol (Δ 9-THC), which instead possesses psychotropic activity and is responsible for the recreative use of hemp. Recently, the homolog s...

Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been repor...

Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the...

Traumatic brain injury (TBI) represents an important public health problem and is followed by neuroinflammation and neurological dysfunctions. It has been suggested that brain trauma is often associated with deep behavioral alterations and chronic pain-like syndrome. Despite inducing minimal brain damage, mild TBI (mTBI) leads to persistent behavio...

Traumatic brain injury (TBI) is one of the main cause of death in young people and currently no drugs to treat brain injury exist. Recently, we have reported that mice with mild-TBI with a specific injury in the insula, showed elevated levels of a little investigated N -acyl amino acid, the N -oleoyl-glycine (OlGly). N -acyl-amino acids have recent...

Aging is a physiological condition involving progressive degenerative modifications and loss of functionality in all organ systems. In general, aged patients are frail and sensitive to anesthesia and surgery. Clinical practice indicates that being more sensitive to anesthetic drugs and more susceptible to the side effects, elderly requires usually...

The butyl homologues of Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabutol (Δ9-THCB), and cannabidiol, cannabidibutol (CBDB), were isolated from a medicinal Cannabis sativa variety (FM2) inflorescence. Appropriate spectroscopic and spectrometric characterization, including NMR, UV, IR, ECD, and HRMS, was carried out on both cannabinoids. The chemical...

(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC its...

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to be...

Significance Understanding the cellular and molecular pathways of neuropathic pain is fundamental to discovering classes of non-opioid analgesics. Emerging evidence implicates altered sphingolipid metabolism and elevated levels of sphingosine-1-phosphate (S1P) in the spinal cord in the persistence of neuropathic pain, but its neuropharmacology and...

Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D...

Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are avai...

This study sought to determine the possible detrimental effects of several low- or non-caloric sweeteners on endothelial progenitor cells (EPCs), inflammation and behavioural changes in mice. C57BL/6 male mice received low and high dose of natural and artificial sweeteners for 4 weeks. EPCs, physical and biochemical variables, inflammation and beha...

Objective The role of the hydroxycarboxylic acid receptor 2 (HCA2) in the retinal damage induced by diabetes has never been explored. In this context, the present study highlights an upregulation of retinal HCA2 receptors in diabetic C57BL6J mice. Moreover, we illustrate that HCA2 receptors exert an anti-inflammatory effect on the retinal damage in...

The discovery of extended catalytic versatilities is of great importance in both the chemistry and biotechnology fields. Fatty acid amide hydrolase (FAAH) belongs to the amidase signature superfamily and is a major endocannabinoid inactivating enzyme using an atypical catalytic mechanism involving hydrolysis of amide and occasionally ester bonds. F...

The mechanisms underlying neuropathic pain are poorly understood. Here we show the unexplored role of the hydroxyl carboxylic acid receptor type 2 (HCAR2) in 2 models of neuropathic pain. We used an oral treatment with dimethyl fumarate and the HCAR2 endogenous ligand β-hydroxybutyrate (BHB) in wild-type (WT) and HCAR2-null mice. We found an up-reg...

The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selec...

Development chemotherapy-induced peripheral neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no FDA-approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in n...

Our previous work discovered that combining the appropriate 5- and N6-substitution in adenosine derivatives leads to highly selective human A1 adenosine receptor (hA1AR) agonists or highly potent dual hA1AR agonists and hA3AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N6-substituted-5-pyrazolyl-adenosine a...

The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, in turn, sensitize nociceptive neurons within the spinal cord. However, t...

Recent findings suggest that soluble forms of amyloid-β (sAß) peptide contribute to synaptic and cognitive dysfunctions in early stages of Alzheimer's disease (AD). On the other hand, neuroinflammation and cyclooxygenase-2 (COX-2) enzyme have gained increased interest as key factors involved early in AD, although the signaling pathways and pathophy...

This chapter describes surgical procedures for the induction of neuropathic pain using an animal model (rat or mouse) of spared nerve injury. In addition to technical details of the surgical technique, details of anesthesia and perioperative care are also included.

The effects of glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), are finely modulated by metabotropic glutamate (mGlu) receptors. The mGlu receptors of group III (mGlu4, mGlu6, mGlu7, and mGlu8) are those less known because of the lack of selective and brain-penetrant ligands. Excepted for mGlu6 receptor, the expr...

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert antiinflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to u...

The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-ind...

Metabotropic glutamate receptors (mGluRs) are key players in modulating excitatory transmission and important regulators of synaptic plasticity. mGluRs are G-protein-coupled receptors (GPCRs) that have been subdivided into three groups (mGluR1–mGluR8) based on sequence homology, intracellular pathways, and pharmacological profile. mGluRs are widely...

Depressive symptoms and other neuropsychiatric dysfunctions are common in neurodegenerative disorders, including chronic pain and dementia. A correlation between the β-amyloid protein accumulation and the development of depression has been suggested, however the underlying mechanisms are unknown. D-Aspartate (D-Asp) is a free D-amino acid found in...

Structural determinants of affinity of N(6)-substituted-5'-C-(ethyl-tetrazol-2-yl)-adenosine and 2-chloro-adenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N(6)-cycloalkyl and 3-halo-benzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent du...

Traumatic brain injury (TBI) represents a major public health problem, which is associated with neurological dysfunction. In severe or moderate cases of TBI, in addition to its high mortality rate, subjects may encounter diverse behavioral dysfunctions. Previous reports suggest that an association between TBI and chronic pain syndromes tends to be...

Neuropathic pain is a neurological disorder that strongly affects the quality of life of patients. The molecular and cellular mechanisms at the basis of the neuropathic pain establishment still need to be clarified. Among the neuromodulators involved in the pathological pain pathways, endocannabinoid system could be deeply involved in both neuronal...

In this study, we investigated the role of the endovanilloid/endocannabinoid system in the glucocorticoid-induced osteoclast overactivity. Receptorial and enzymatic component of the endovanilloid/endocannabinoid system are expressed in bone cells, and dysregulated when bone mass is reduced. Moreover, blockade or desensitization of vanilloid recepto...

Objectives: In taekwondo competitions, fatigue has a large influence on performance. Recent studies have reported that the excitability in the primary hand motor cortex, investigated with transcranial magnetic stimulation (TMS), is enhanced at the end of a maximal exercise and that this improvement correlates with blood lactate. The aim of the pre...

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a mode...

The modulatory actions of glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), are exerted through the activation of metabotropic glutamate receptors (mGluRs). Of the eight known mGluRs (mGluR1-8), group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) are less understood because of the lack of selective ligands. Exce...

Context: Obesity is associated with a low-grade inflammatory state, and adipocyte hyperplasia/hypertrophy. Obesity inhibits the "browning" of white adipose tissue. Cannabinoid receptor 2 (CB2) agonists reduce food intake and induce anti-obesity effect in mice. A common missense CB2-variant, Q63R, causes CB2 reduced function. Objective: To evalua...

Eleven compounds belonging to the chalcone family were tested for their ability to activate and subsequently desensitise the rat transient receptor potential ankyrin 1 cation channel, subfamily A, member 1 (TRPA1) in a heterologous expression system. Four of the tested compounds were more potent than the TRPA1 agonist mustard oil, and showed also a...

The endogenous NMDA receptor (NMDAR) agonist D-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral D-aspartate levels is due to the concomitant onset of D-aspartate oxidase (DDO) ac...

4-(Thiophen-2-yl)butanoic acid was identified as a cyclic substitute of the unsaturated alkyl chain of the natural ligand, capsaicin. Accordingly, a new class of amides was synthesized in good yield and high purity and their molecular recognition against the target was investigated by means of docking experiments followed by molecular dynamics simu...