An Italian Survey and Focus Groups on Fibromyalgia Impairment: Impact on Work and Possible Reasonable Accommodations.

Fibromyalgia symptoms affect the sufferers' working life; however, through reasonable accommodations in workplaces, they can continue to work satisfactorily. There are no Italian studies on factors that facilitate or hinder fibromyalgia-affected people's working life. Our objective was to explore, in a pre-pandemic setting, the quality of working life of fibromyalgia sufferers and reasonable accommodations to improve it. Quantitative and qualitative methods were applied; a survey-questionnaire, participatory-developed, was online-administered to a sample of self-reported FM sufferers (N = 1176). Then, two Focus Groups (FGs), involving 15 fibromyalgia-affected women, were held. Data were analyzed by a thematic analysis approach. Among survey-respondents, 20% were unemployed and only 14% went to work gladly. Variability of pain (84%) and fatigue (90%) were the most perceived reasons for difficulties at work. Negative relationships at work were reported by most participants. The FGs' discussions addressed different strategies for overcoming the main obstacle of "not being believed by colleagues and employers" and reasonable accommodations. However, a negative hopeless attitude towards the solution of problems at work was also apparent. Different critical issues in the workplace emerged from the survey and the FGs. Coordinated actions, according to a transdisciplinary approach, are needed to manage fibromyalgia-induced difficulties in the workplace.

A Nutritional Supplement as Adjuvant of Gabapentinoids for Adults with Neuropathic Pain following Spinal Cord Injury and Stroke: Preliminary Results.

Gabapentinoids are first choice drugs for central neuropathic pain (CNP) despite limited evidence of efficacy and side effects affecting therapy outcomes. Nutraceuticals could improve their efficacy and tolerability. Our aim is to investigate the effect of NACVAN®, in addition to gabapentinoids, on pain symptomatology in CNP patients. The effect of 6 weeks of treatment of NACVAN® was preliminary observed among 29 adult inpatients with spinal cord injury (SCI) or stroke-related CNP recruited to the experimental group. Pain intensity, neuropathic pain, and quality-of-life were measured at baseline (T0) and after 3 (T1) and 6 weeks (T2). Change in each outcome over time was assessed through a repeated measures analysis of variance or Wilcoxon matched-pairs test. Preliminary results show a significant reduction in pain intensity (T0 → T1, p = 0.021; T0 → T2, p = 0.011; T1 → T2, p = 0.46), neuropathic symptoms (T0 → T1, p = 0.024; T0 → T2, p = 0.003), and evoked pain (T0 → T2, p = 0.048). There were no significant reductions in other neuropathic pain dimensions and in quality-of-life components. No side-effects were detected. NACVAN® could have a beneficial adjuvant effect when used as an add-on to gabapentinoids in patients suffering from CNP due to SCI or stroke, with no adverse effect. Future analysis on a larger sample, compared with a placebo condition, could confirm these preliminary results.

Fibromyalgia and Irritable Bowel Syndrome Interaction: A Possible Role for Gut Microbiota and Gut-Brain Axis.

Fibromyalgia (FM) is a serious chronic pain syndrome, characterised by muscle and joint stiffness, insomnia, fatigue, mood disorders, cognitive dysfunction, anxiety, depression and intestinal irritability. Irritable Bowel Syndrome (IBS) shares many of these symptoms, and FM and IBS frequently co-exist, which suggests a common aetiology for the two diseases. The exact physiopathological mechanisms underlying both FM and IBS onset are unknown. Researchers have investigated many possible causes, including alterations in gut microbiota, which contain billions of microorganisms in the human digestive tract. The gut-brain axis has been proven to be the link between the gut microbiota and the central nervous system, which can then control the gut microbiota composition. In this review, we will discuss the similarities between FM and IBS. Particularly, we will focus our attention on symptomatology overlap between FM and IBS as well as the similarities in microbiota composition between FM and IBS patients. We will also briefly discuss the potential therapeutic approaches based on microbiota manipulations that are successfully used in IBS and could be employed also in FM patients to relieve pain, ameliorate the rehabilitation outcome, psychological distress and intestinal symptoms.

An Observational Study on Chronic Pain Biomarkers in Fibromyalgia and Osteoarthritis Patients: Which Role for Mu Opioid Receptor's Expression on NK Cells?

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells' functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the "Mu opioid receptor reserve theory".

A Systematic Review and Meta-Analysis on the Role of Nutraceuticals in the Management of Neuropathic Pain in In Vivo Studies.

The control of neuropathic pain is a leading challenge in modern medicine. Traditional medicine has, for a long time, used natural compounds such as nutraceuticals for this purpose, and extensive evidence has supported their role in controlling oxidative stress and persistent pain-related inflammation. Nutraceuticals are natural products belonging to the food sector whose consumption could be related to physiological benefits. Indeed, they are used to improve health, prevent chronic diseases, and delay the aging process. Here, we report a systematic review and meta-analysis to provide a more comprehensive report on the use of nutraceuticals in neuropathic pain, including evaluating confounding factors. A search of the literature has been conducted on principal databases (PubMed, MEDLINE, EMBASE, and Web of Science) following the PRISMA statement, and we retrieved 484 articles, 12 of which were selected for the meta-analysis. The results showed that administration of natural drugs in animals with neuropathic pain led to a significant reduction in thermal hyperalgesia, measured in both the injured paw (SMD: 1.79; 95% CI: 1.41 to 2.17; p < 0.0001) and in the two paws (SMD: −1.74; 95% CI: −3.36 to −0.11; p = 0.036), as well as a reduction in mechanical allodynia and hyperalgesia (SMD: 1.95, 95% CI: 1.08 to 2.82; p < 0.001) when compared to controls. The results of the review indicate that nutraceutical compounds could be clinically relevant for managing persistent neuropathic pain.

Tantali fibromyalgic supplicium: Is there any relief with the antidepressant employment? A systematic review.

Widespread musculoskeletal pain characterizes fibromyalgia (FM), accompanied by sleep, fatigue, and mood problems. Chronic stress and depression play a crucial role in the etiology and pathophysiology of FM. They may contribute to a dysregulation of the central pain mechanisms together with the neuroendocrine and immune systems. Pharmacological treatments are the first-line therapy to reduce the symptoms of FM. The US Food and Drug Administration (FDA) indicated gabapentinoid, pregabalin, duloxetine, and milnacipran for adult patients. An alternative approach is widely used, based on therapies including interventions in patient education, behavioral therapy, exercise, pain management, and a healthy diet. A systematic search was performed on PubMed, MEDLINE, EMBASE, and Web of Science databases. The authors established the selection, inclusion, and exclusion criteria. We found a total of 908 articles. This systematic review will include ten articles selected after excluding duplicates and reading the abstracts and full texts. All studies related the effect of drugs to various symptoms caused by fibromyalgia patients with depression, such as insomnia/sleepiness, depression, suicide, difficulty walking/working, pain, fatigue, and nervousness. Although, we concluded that antidepressant drugs are effective in treating depression and pain in fibromyalgia, further studies are needed to understand the etiology of this disease and to find a combination of therapies to increase tolerability and adherence of the patient to the drug, decreasing the adverse effects.

An Italian Twin Study of Non-Cancer Chronic Pain as a Wide Phenotype and Its Intensity.

Background and Objectives: Non-cancer chronic pain (CP) results from the interaction between genetic and environmental factors. Twin studies help to estimate genetic and environmental contributions to complex traits such as CP. To date, twin studies on the heritability of pain phenotypes have relied almost exclusively on specific diagnoses, neglecting pain intensity. This study aims to estimate the genetic and environmental contributions to CP occurrence as a wide phenotype and its intensity among a non-clinical population. Materials and Methods: A nationwide online survey was conducted in February 2020 on 6000 adult twins enrolled in the Italian Twin Registry. A five-item questionnaire, designed and validated by our study group, was administered to detect the CP condition along with its intensity, underlying causes or triggers, treatments, and self-perceived efficacy. The twin study design was used to infer the relative weight of genes and environment on CP occurrence and intensity, and biometrical modelling was applied to these phenotypes. Results: A total of 3258 twins, aged ≥18, replied to the online survey (response rate 54%). These included 762 intact pairs (mean age: 39 years; age range: 18-82 years; 34% male; CP prevalence: 24%), of whom 750 pairs were subjected to biometrical modelling after the exclusion of pairs with either unknown zygosity or cancer-associated CP. Broad-sense heritability estimates were driven by non-additive genetic effects and were 0.36 (0.19-0.51) for CP occurrence and 0.31 (0.16-0.44) for CP intensity. No evidence emerged for either sex differences in genetic and environmental variance components or interactions of these components with age. Conclusions: Moderate non-additive genetic components were suggested for non-cancer CP occurrence and its intensity. These results encourage further research on the gene-gene interactions underlying CP liability and associated phenotypes, and also strengthen the need for prevention strategies to avoid CP occurrence or to decrease pain intensity.

Development and Validation of the Italian "Brief Five-Item Chronic Pain Questionnaire" for Epidemiological Studies.

Background: Chronic pain (CP) prevalence estimates addressing a wide phenotype are still quite fragmented and may vary widely due to the lack of standardized tools of investigation. There is an urgent need to update general population CP estimates. Methods: For this purpose, the Brief Five-item Chronic Pain Questionnaire was developed through experts' consultations for design and content validity assessment; literature analysis of measures used to investigate CP for general population surveys; understandability evaluation through a survey on a convenience sample of affected and non-affected individuals; reliability assessment by means of two double-wave online surveys carried out by the Italian Twin Registry; criterion and construct validity assessment through the third wave of the 2019 European Health Interview Survey (Ehis). Results: Key dimensions were defined to describe CP main aspects from a public health perspective. Literature analysis showed that validated questionnaires were rarely used to address important public health CP aspects. Understandability of the measure was good. Test-retest analyses showed adequate reliability of the measure: k values were at least "moderate" with highest values regarding CP "occurrence" and "intensity". Correlations of CP with well-known comorbidities (cancer, depression), and specific traits (age, education) as well as of CP and its intensity with "physical pain occurrence and intensity" detected in the Ehis 2019, confirmed, respectively, a good construct and criterion validity. Construct validity was also evaluated through the correlation between "perceived treatment effectiveness" and "interference of pain in daily life activities" as recorded in the Ehis 2019. Conclusion: The designed questionnaire is a brief self-administered measure, particularly suitable to detect persistent states of pain and related intensity in large-scale general population surveys by means of a first filtering item followed by four further items. It is, in fact, designed to detect CP possible underlying causes/triggers, drugs/treatments taking and frequency, and self-perceived effectiveness among CP sufferers. Further validation of the measure in different social and cultural contexts is desirable.

Common-sense model of self-regulation to cluster fibromyalgia patients: results from a cross-sectional study in Italy.

OBJECTIVES: Fibromyalgia is a severe and disabling chronic pain syndrome affecting millions of people worldwide. Various patients' subgroups were identified using different atheoretical measures, hardly effective to tailor treatments. Previous literature findings showed the relevance of fibromyalgia patients' illness perceptions in adjusting to the disease. The present study aims to identify clusters of fibromyalgia patients based on their illness perceptions and investigate whether they can differ across pain, mood, physical functioning, catastrophising, and pain acceptance measures. METHODS: Fifty-three newly referred fibromyalgia patients completed clinical and psychological questionnaires. Patients' subgroups were created by applying hierarchical cluster analysis to their answers to Illness Perception Questionnaire-Revised subscales. Potential differences across subgroups in outcome variables were tested. RESULTS: Cluster analysis identified two patient groups. Group A (32 patients) had a higher representation of fibromyalgia as a chronic disease with severe consequences, lower beliefs in personal and treatment control, and a higher fibromyalgia-related emotional distress than group B (21 patients). Clusters did not differ on pain intensity and duration. Group A, compared to group B, showed worse physical functioning and overall impairment due to fibromyalgia, a poorer psychological condition, a higher tendency to catastrophise, and less pain acceptance. CONCLUSIONS: Study findings reveal two fibromyalgia subgroups differing in emotional suffering and impairment despite similar pain intensity and duration. Patients' illness perceptions and attitudes towards pain, like catastrophising and acceptance, might be critical in adjusting to the disease. A detailed assessment of such risk and protective factors is critical to differentiate patients' subgroups with different needs and thus offering tailored treatments.

The Dorsomedian Ligamentous Strand: An Evaluation In Vivo with Epiduroscopy.

Several anatomical studies have described the morphology of the spinal space; however, researchers do not all agree on the presence of the dorsomedian ligamentous strand (DLS), which divides the epidural space. The possible existence of this structure still influences some clinical practice, such as locoregional anesthesia and pain therapy. Since the number of procedures occurring inside the epidural space have increased, this study's primary objective was to describe the composition of this space through epiduroscopy. We conducted a retrospective analysis of video recorded during epiduroscopy. Two independent doctors performed blind analyses of morphological aspects of peridural space visualized during the procedure in each patient for the maximum possible extension depending on the underlying pathology in the tract from S1 to L1. We enrolled 106 patients who underwent epiduroscopy; 100% of patients presented no medial longitudinal segmentation dividing the epidural channel at any level of the spinal tract investigated, including in the epidural space with pathological fibrotic scars and in those with no adherence. The main finding of our study was the visual absence of any anatomical structure dividing the epidural channel. We report that in vivo, in our experience, with direct epiduroscopy, the DLS is not visible.

A Narrative Review of the Assessment of Depression in Chronic Pain.

OBJECTIVES: This narrative review sought to explore the main critical issues in the assessment of depression in chronic pain and to identify self-report tools that can be reliably used for measuring it. DESIGN: Narrative review of the literature. METHODS: Articles were obtained through a search of three databases and a hand search of the references of full-text papers. Key results within the retrieved articles were summarized and integrated to address the review objectives. RESULTS: Criterion contamination, different ways to define and evaluate pain and depression across studies, variability in chronic pain samples and settings, pitfalls of diagnostic systems and self-reports, and reluctance to address (or difficulty of recognizing) depression in patients and healthcare providers emerged as main critical issues. The Beck Depression Inventory seems to be the more accurate tool to evaluate depression in chronic pain patients, while other instruments such as the Patient Health Questionnaire could be recommended for a rapid screening. CONCLUSIONS: Assessment of depression comorbidity in chronic pain represents a challenge in both research and clinical practice; the choice and use of tests, as well as the score interpretation, require clinical reasoning. NURSING PRACTICE IMPLICATIONS: Nurses play an important role in screening for depression. Cognitive contents of depression should be carefully evaluated since somatic symptoms may be confusing in the chronic pain context. Some self-reports may be useful for rapid screening. It is also advisable to consider other relevant patient information in evaluating depression.

The Interplay between Chronic Pain, Opioids, and the Immune System.

Chronic pain represents one of the most serious worldwide medical problems, in terms of both social and economic costs, often causing severe and intractable physical and psychological suffering. The lack of biological markers for pain, which could assist in forming clearer diagnoses and prognoses, makes chronic pain therapy particularly arduous and sometimes harmful. Opioids are used worldwide to treat chronic pain conditions, but there is still an ambiguous and inadequate understanding about their therapeutic use, mostly because of their dual effect in acutely reducing pain and inducing, at the same time, tolerance, dependence, and a risk for opioid use disorder. In addition, clinical studies suggest that opioid treatment can be associated with a high risk of immune suppression and the development of inflammatory events, worsening the chronic pain status itself. While opioid peptides and receptors are expressed in both central and peripheral nervous cells, immune cells, and tissues, the role of opioids and their receptors, when and why they are activated endogenously and what their exact role is in chronic pain pathways is still poorly understood. Thus, in this review we aim to highlight the interplay between pain and immune system, focusing on opioids and their receptors.

A Review of the Clinical and Therapeutic Implications of Neuropathic Pain.

Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease.

Opportunities and challenges for nonaddictive interventions in chronic pain.

The worlds of chronic pain and addiction continue to intersect too often in many ways. Chronic pain significantly impairs and disrupts the quality of life of millions of people worldwide. Opioids remain the most prescribed pharmacotherapy offered to patients to alleviate chronic pain. The extensive and often unnecessary prescription of opioids has created a surge in the prevalence of opioid use disorders and opioid overdose-related deaths. In this brief review, we aim to provide a bench-to-bedside overview of promising biomarkers, therapeutic targets, and challenges related to treating patients with chronic pain. We hope this review will inspire new opportunities and insights into the development of novel, nonaddictive treatments for chronic pain that will be available to patients in the near future.

Asperuloside Enhances Taste Perception and Prevents Weight Gain in High-Fat Fed Mice.

Asperuloside is an iridoid glycoside found in many medicinal plants that has produced promising anti-obesity results in animal models. In previous studies, three months of asperuloside administration reduced food intake, body weight, and adipose masses in rats consuming a high fat diet (HFD). However, the mechanisms by which asperuloside exerts its anti-obesity properties were not clarified. Here, we investigated homeostatic and nutrient-sensing mechanisms regulating food intake in mice consuming HFD. We confirmed the anti-obesity properties of asperuloside and, importantly, we identified some mechanisms that could be responsible for its therapeutic effect. Asperuloside reduced body weight and food intake in mice consuming HFD by 10.5 and 12.8% respectively, with no effect on mice eating a standard chow diet. Fasting glucose and plasma insulin were also significantly reduced. Mechanistically, asperuloside significantly reduced hypothalamic mRNA ghrelin, leptin, and pro-opiomelanocortin in mice consuming HFD. The expression of fat lingual receptors (CD36, FFAR1-4), CB1R and sweet lingual receptors (TAS1R2-3) was increased almost 2-fold by the administration of asperuloside. Our findings suggest that asperuloside might exert its therapeutic effects by altering nutrient-sensing receptors in the oral cavity as well as hypothalamic receptors involved in food intake when mice are exposed to obesogenic diets. This signaling pathway is known to influence the subtle hypothalamic equilibrium between energy homeostasis and reward-induced overeating responses. The present pre-clinical study demonstrated that targeting the gustatory system through asperuloside administration could represent a promising and effective new anti-obesity strategy.

Chronic Pain: What Does It Mean? A Review on the Use of the Term Chronic Pain in Clinical Practice.

Chronic pain is nowadays used as an umbrella term referring to a wide range of clinical conditions, such as fibromyalgia, migraine, or long-standing pain states without actual known causes. However, labeling a patient's clinical condition with the term "chronic pain", when dealing with pain lasting longer than 3 months, might be misleading. This paper aims at analyzing the possible pitfalls related to the use of the term "chronic pain" in the clinical field. It appears, indeed, that the term "chronic pain" shows a semantic inaccuracy on the basis of emerging scientific evidences on the pathogenesis of different long-standing pain states. The major pitfalls in using this label emerge in clinical settings, especially with patients having a biomedical perspective on pain or from different cultures, or with healthcare providers of other medical specialties or different disciplines. A label solely emphasizing temporal features does not help to discern the multifaceted complexity of long-standing pain states, whose onset, maintenance and exacerbation are influenced by a complex and interdependent set of bio-psycho-social factors. Thus, finding a more meaningful name might be important. We call upon the necessity of bringing awareness and implementing educational activities for healthcare providers, as well as for the public, on the biopsychosocial approach to assess, prevent and care of chronic pain. Further research on the etiopathogenetic processes of chronic pain states is also required, together with examinative diagnostic methods, to individuate the most appropriate label(s) representing the complex long-standing pain states and to avoid adopting the term "chronic pain" inappropriately.

Identification of MOR-Positive B Cell as Possible Innovative Biomarker (Mu Lympho-Marker) for Chronic Pain Diagnosis in Patients with Fibromyalgia and Osteoarthritis Diseases.

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease.

Lymphocyte opioid receptors as innovative biomarkers of osteoarthritic pain, for the assessment and risk management of opioid tailored therapy, before hip surgery, to prevent chronic pain and opioid tolerance/addiction development: OpMarkArt (Opioids-Markers-Arthroprosthesis) study protocol for a randomized controlled trial.

BACKGROUND: The incidence of post-surgical chronic pain ranges between 20% and 40% in Europe. Osteoarthritis pain after prosthesis implantation is one of the most severe secondary syndromes, depending not only on surgery but also on organic changes before and after joints replacement. No data are available about risk factors. An excessive inflammatory response plays a central role but a best therapy is not defined yet. It is not clear whether opioid administration could influence post-surgical pain and lead to tolerance or addiction. Interestingly, the immune system, together with the nervous and peptidergic ones, is involved in hypersensibility. The connection across the three biological systems lies in the presence of opioid receptors on immune cells surface. Here, we show a method to analyze whether opioids could modulate lymphocytes, by proposing opioid receptors as biological markers to prevent chronic pain and opioid tolerance or addiction after hip surgery. METHODS/DESIGN: After institutional independent ethics committee approval, 60 patients, in pain and undergoing hip surgery, will be enrolled in a single-blind, randomized, phase IV, pilot study. Pain treatment will be selected inside a class of non-steroidal anti-inflammatory drugs (NAISDs) or paracetamol or a class of opioids, into three medication arms: 25 mg tapentadol twice daily; 75 mg tapentadol twice daily; NSAIDs or paracetamol in accordance with surgeon's custom. For each group, we will collect blood samples before, during and after surgery, to apply molecular analysis. We will perform lymphocyte opioid receptors genes and proteins expression and functional analysis. Data will be statistically analyzed. DISCUSSION: This project has the potential to obtain a personalized diagnostic kit, by considering lymphocyte opioid receptors as biological markers. Starting from a simple blood sample, it will be possible to decide the best therapy for a single patient. Using a noninvasive approach, we expect to fix a daily standard dose and timing, before and after surgery, to bypass hip chronic pain and the insurgence of tolerance or addiction. The analysis of opioid receptors sensitivity will help to identify the best drug administration in each specific case (tailored therapy). TRIAL REGISTRATION: ISRCTN, ISRCTN12559751 . Retrospectively registered on 23 May 2017.

Pain as a disease: an overview.

The acknowledgment of pain as a pathologic entity in its own right remains debated. Notwithstanding the data showing the burden of pain as a disease, an ultimate recognition of the pathologic nature of this condition is lacking. In this study, we analyze the notion of pain as a disease through an historical overview of its several conceptualizations and report the main evidence supporting this notion. We believe that a clear definition of pain as a disease is necessary, especially considering the enormous global burden of this condition. Indeed, the recognition of pain as a definite pathologic state is crucial to raise awareness about this neglected global health problem and to promote the exploration of new specific therapeutic approaches.

Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.