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

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"

Pain assessment in animal models: do we need further studies?

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals

“THERMAL NOCICEPTION STUDIES IN ZEBRAFISH”

Background Nociception was defined by Sherrington as the mechanism used to sense painful events. Despite the value of current animal models for nociception and pain, we have not yet understood in full how these mechanisms operate. Aim Here we propose a novel approach using zebrafish (Danio rerio) larvae in order to determine if the fish is suitable for the study of pain stimuli. Taking advantage of the fact that, in response to noxious stimuli, the expression of several genes in mammals is induced in neurons of the spinal cord and the dorsal root ganglia (DRG), we investigated if such mechanism is evolutionary conserved in the Zebrafish. Materials and Methods We cloned homologues of mammals pain marker genes (PMGs) in the fish and we tested their expression after painful stimuli. Thus, we determined an easy and ubiquitous method of noxious stimuli induction in 5dpf larvae by heat shock. We quantitatively assayed these larvae for over-expression of the PMGs by real-time PCRs, to determine if any of these genes is up regulated in specific time points. In another set of experiments we tested, by in situ hybridization, the localization of the PGMs over-expression in the larvae. To confirm the up-regulation of these genes is pain related we looked for the possible heat receptor that could mediate such sensation. Thus, we cloned Zebrafish trpv1, analyzed the expression pattern, tested its function with loss of function experiment and by analysis of changes in intracellular calcium levels after various painful stimuli in HEK293T cell line. Results and Conclusions These experiments show peculiar over-expression of all the PMGs in time and space, in particular they are expressed in what are probably the spinal cord and the DGR. We cloned and studied trpv1 as a good candidate for heat sensation mediation. However, zebrafish trpv1 responds only to low pH when tested in human cell line. Thus, we need further in vivo analysis to determine if trpv1 cooperates with other factors to mediate noxious heat in zebrafish

Using 3D virtual surfaces to investigate molluscan shell shape

Noninvasive methods in shell shape variation may help to understand evolution, ecology, stress and role of molluscan in aquatic ecosystems. Imaging analysis is a suitable diagnostic tool in morphological studies to (1) evaluate the health status of investigated animals, and (2) monitor sea coastal habitats. We introduce the feasibility of the cone-beam computed tomography as an optimal technique for 3D surface scanning to obtain virtual valve surfaces of Mytilus galloprovincialis, and analyze them exploiting the geometric morphometric facilities. Statistical output revealed morphological difference between mussels coming from different extensive rearing systems highlighting how the entire valve surface contributed to discriminate between groups when we compared 2- and 3D analyses. Many factors drive the morphological differences observed in the valve shape variation between the two sites, such as geographical genetic differentiation, natural environmental effects and culture conditions. The simplicity of the proposed methodology avoids damage and handling of individuals, makes this approach useful for morphological data collection, and helps to detect detrimental agents for sea ecosystems by using molluscans

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

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

Objective 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.MethodsFifty-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.ResultsCluster 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 fibromyalgiarelated 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.ConclusionStudy 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 offer tailored treatments

Mild Cognitive Impairment and Mild Dementia: The Role of Ginkgo biloba (EGb 761®)

Mild cognitive impairment (MCI) and dementia are clinically prevalent in the elderly. There is a high risk of cognitive decline in patients diagnosed with MCI or dementia. This review describes the effectiveness of Ginkgo biloba leaf special extract EGb 761® for the treatment of dementia syndromes and EGb 761® combination therapy with other medications for symptomatic dementia. This drug has shown convincing results, improving cognitive function, neuropsychiatric symptoms and consequent reduction of caregiver stress and maintenance of autonomy in patients with age-related cognitive decline, MCI and mild to moderate dementia. Currently, there is little evidence to support the combination therapy with anti-dementia drugs and, therefore, more evidence is needed to evaluate the role of EGb 761® in mixed therapy