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Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG. Transcriptional changes occur in the dorsal root ganglion in response to nerve injury and may contribute to neuropathic pain. Here the authors show that the DNA methyltransferase DNMT3a is upregulated in rodents following nerve injury, and may contribute to pain-like behaviour by decreasing expression of the voltage-gated potassium channel Kv1.2.

The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice.

Background SNAP-25 protein is contributory to plasma membrane and synaptic vesicle fusions that are critical points in neurotransmission. SNAP-25 gene is associated with behavioral symptoms, personality and psychological disorders. In addition, SNAP-25 protein can be related to different neurotransmitter functions due to its association with vesicle membrane transition and fusion. This is important because neurologic, cognitive, and psychologic disorders in fibromyalgia syndrome (FMS) can be related to this function. This relationship may be enlightening for etiopathogenesis of FMS and treatment approaches. We aimed to study a SNAP-25 gene polymorphism, which is related to many psychiatric diseases, and FMS association in this prospective study. Methods We included 71 patients who were diagnosed according to new criteria and 57 matched healthy women in this study. Both groups were evaluated regarding age, height, weight, BMI, education level, marital and occupational status. A new diagnosis of FMS was made from criteria scoring, SF-36, Beck depression scale, and VAS that were applied to the patient group. SNAP-25 gene polymorphism and disease activity score correlations were compared. Results Mean age was 38±5,196 and 38.12±4.939 in patient and control groups, respectively (p=0.542). No significant difference was found between groups regarding age, height, weight, BMI, education level, marital or occupational status (p > 0.05). Ddel T/C genotype was significantly higher in the patient group (p = 0.009). MnlI gene polymorphism did not show a correlation with any score whereas a significant correlation was found between Ddel T/C genotype and Beck depression scale and VAS score (p < 0.05). Conclusion FMS etiopathogenesis is not clearly known. Numerous neurologic, cognitive and psychological disorders were found during studies looking at cause. Our study showed increased SNAP-25 Ddel T/C genotype in FMS patients compared to the control group, which is related to behavioral symptoms, personality and psychological disorders in FMS patients.

Fibromyalgia is a syndrome characterized by chronic and widespread musculoskeletal pain, often accompanied by other symptoms, such as fatigue, intestinal disorders and alterations in sleep and mood. It is estimated that two to eight percent of the world population is affected by fibromyalgia. From a medical point of view, this pathology still presents inexplicable aspects. It is known that fibromyalgia is caused by a central sensitization phenomenon characterized by the dysfunction of neuro-circuits, which involves the perception, transmission and processing of afferent nociceptive stimuli, with the prevalent manifestation of pain at the level of the locomotor system. In recent years, the pathogenesis of fibromyalgia has also been linked to other factors, such as inflammatory, immune, endocrine, genetic and psychosocial factors. A rheumatologist typically makes a diagnosis of fibromyalgia when the patient describes a history of pain spreading in all quadrants of the body for at least three months and when pain is caused by digital pressure in at least 11 out of 18 allogenic points, called tender points. Fibromyalgia does not involve organic damage, and several diagnostic approaches have been developed in recent years, including the analysis of genetic, epigenetic and serological biomarkers. Symptoms often begin after physical or emotional trauma, but in many cases, there appears to be no obvious trigger. Women are more prone to developing the disease than men. Unfortunately, the conventional medical therapies that target this pathology produce limited benefits. They remain largely pharmacological in nature and tend to treat the symptomatic aspects of various disorders reported by the patient. The statistics, however, highlight the fact that 90% of people with fibromyalgia also turn to complementary medicine to manage their symptoms.

The intensity of acute and chronic pain depends on interactions between peripheral impulse input and CNS pain mechanisms, including facilitation and inhibition. Whereas tonic pain inhibition is a characteristic of most pain-free individuals, pain facilitation can be detected in many chronic pain patients. The capability to inhibit pain is normally distributed along a wide continuum in the general population and can be used to predict chronic pain. Accumulating evidence suggests that endogenous pain inhibition depends on activation of the prefrontal cortex, periaqueductal gray and rostral ventral medulla. Quantitative sensory test paradigms have been designed to acquire detailed information regarding each individual's endogenous pain inhibition and facilitation. Such tests include: temporal summation of pain, which is mostly used to assess facilitatory pain modulation by measuring the change in pain perception during a series of identical nociceptive stimuli; and conditioned pain modulation, which tests pain inhibition by utilizing two simultaneously applied painful stimuli (the 'pain inhibits pain' paradigm). Considerable indirect evidence seems to indicate that not only increased pain facilitation but also ineffective pain inhibition represents a predisposition for chronic pain. This view is supported by the fact that many chronic pain syndromes (e.g., fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, headache and chronic fatigue syndrome) are associated with hypersensitivity to painful stimuli and reduced endogenous pain inhibition. However, future prospective studies will be necessary to provide definitive evidence for this relationship. Such research would not only provide important information about mechanisms relevant to chronic pain but would also permit identification of individuals at high risk for future chronic pain.

Understanding the mechanisms of migraine remains challenging as migraine is not a static disorder, and even in its episodic form migraine remains an “evolutive” chronic condition. Considerable progress has been made in elucidating the pathophysiological mechanisms of migraine, associated genetic factors that may influence susceptibility to the disease, and functional and anatomical changes during the progression of a migraine attack or the transformation of episodic to chronic migraine. Migraine is a life span neurological disorder that follows an evolutive age-dependent change in its prevalence and even clinical presentations. As a disorder, migraine involves recurrent intense head pain and associated unpleasant symptoms. Migraine attacks evolve over different phases with specific neural mechanisms and symptoms being involved during each phase. In some patients, migraine can be transformed into a chronic form with daily or almost daily headaches. The mechanisms behind this evolutive process remain unknown, but genetic and epigenetic factors, inflammatory processes and central sensitization may play an important role.

Many musculoskeletal pain conditions are characterized by hypersensitivity, which is induced by central sensitization (CS). A questionnaire, the Central Sensitization Inventory (CSI), was recently developed to help clinicians identify patients whose presenting symptoms may be related to central sensitivity syndrome (CSS). The aims of the present study were to examine criterion validity and construct validity of the Japanese version of the CSI (CSI-J), and to investigate prevalence rates of CS severity levels in patients with musculoskeletal disorders. Translation of the CSI into Japanese was conducted using a forward-backward method. Two hundred and ninety patients with musculoskeletal pain disorders completed the resultant CSI-J. A subset of the patients (n = 158) completed the CSI-J again one week later. The relationships between CSI and clinical symptoms, EuroQol 5-dimension (EQ-5D) and Brief Pain Inventory (BPI), were examined for criterion validity. EQ-5D assesses Health-related QOL and BPI measures pain intensity and pain interference. The psychometric properties were evaluated with analyses of construct validity, factor structure and internal consistency, and subsequently investigate the prevalence rates of CS severity levels. The CSI-J demonstrated high internal consistency (Cronbach's α = 0.89) and test-retest reliability was excellent value (ICC = 0.85). The CSI-J was significantly correlated with EQ-5D (r = -0.44), pain intensity (r = 0.42), and pain interference (r = 0.48) (p < 0.01 for all). Ten percent of the participants were above the cutoff \"40\". The exploratory factor analysis resulted in 5-factor model. This study reported that the CSI-J was a useful and psychometrically sound tool to assess CSS in Japanese patients with musculoskeletal disorders. The finding of the prevalence rates of CS severity levels in patients with musculoskeletal disorders may help clinicians to decide strategy of treatment.

This study aimed to investigate the frequency of CS and its clinical and functional effects on familial Mediterranean fever (FMF). A hundred FMF patients were included in this study. The presence of CS was investigated by the central sensitization inventory (CSI). In addition to the detailed clinical features of patients and genetic mutations, quality of life, disability, sleep disorders, depression, anxiety, and fibromyalgia frequency were examined to evaluate the negative effects of CS on the individual. Patients were divided into groups according to the presence and severity of CS, and their results were compared. Correlation and multivariate regression analysis were performed to investigate the association of CS with selected demographic and clinical parameters. The mean CSI was 37.72 (SD: 19.35), and thirty-eight (38%) patients had CS. Sacroiliitis occurred in 11 patients (11%), amyloidosis in 3 (3%), and erysipelas-like erythema in 11 (11%). The most prevalent genetic mutation was M694/any compound heterogeneous (35.7%), followed by M69V homogeneous (30%). Regarding comparing the patients with and without CS, the number of attacks, disease activity, daily colchicine dose, and all investigated comorbidities were significantly higher in the patients with CS (p < 0.05). In regression analysis, gender, colchicine dose and sleep disturbance were detected as related parameters with CS (OR (95% CI): 6.05 (1.39; 26.32), p: 0.017, OR (95% CI): 6.69 (1.65; 27.18), p: 0.008, OR (95% CI): 1.35 (1.35; 1.59), p: 0.001, respectively). Concomitant pain sensitization appears to be related to FMF patients' clinical and functional characteristics. These results suggest taking into consideration CS in the management of FMF patients.

Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular cartilage degeneration and chronic pain. Research into OA animal models suggests that elevated NGF levels in the synovium contribute to pain and central sensitization (CS). However, it is unclear whether synovial NGF contributes to CS in patients with OA. We investigated the association between synovial NGF expression and clinical assessments of pain and CS in hip OA (hOA) patients. We also aimed to identify which cells in the synovium of hOA patients express NGF. Sixty-six patients who received total hip replacement and a diagnosis of hOA were enrolled. We measured NGF mRNA expression in synovial samples obtained from 50 patients using qPCR and analyzed the correlation of NGF expression with the CS inventory (CSI) score and Japanese Orthopaedic Association (JOA) score, a clinical scoring system for OA. To identify the synovial cells expressing NGF, we analyzed NGF mRNA expression in CD14+ and CD14- cells, which represent macrophage-rich and fibroblast-rich fractions, respectively, extracted from 8 patients. To further identify which macrophage subtypes express NGF, we examined NGF mRNA expression in CD14high and CD14low cells sorted from 8 patients. Synovial NGF mRNA expression was negatively correlated with JOA score but positively correlated with CSI score (JOA pain, r=−0.337, P=0.017; CSI score, r=0.358, P=0.011). Significantly greater levels of NGF were observed in CD14- cells compared to CD14+ cells (P=0.036) and in CD14high cells compared to CD14low cells (P=0.008). In conclusion, synovial NGF expression is correlated with the degree of pain and CS in hOA patients. NGF is predominantly expressed in synovial fibroblasts. Further, CD14high synovial macrophages expressed higher levels of NGF. Our results may provide a novel NGF-targeted therapeutic strategy for hOA pain.