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Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects and selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure-activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.
Learn More >Chronic widespread pain (CWP) including fibromyalgia has a prevalence of up to 15% and is associated with substantial morbidity. Supporting psychosocial and behavioural self-management is increasingly important for CWP, as pharmacological interventions show limited benefit. We systematically reviewed the effectiveness of interventions applying self-management principles for CWP including fibromyalgia.
Learn More >Localized provoked vulvodynia (LPV) causes dyspareunia among reproductive aged women. We review the pathogenesis of LPV and suggest that LPV is an inflammatory pain syndrome of the vestibular mucosa triggered by microbial antigens in a susceptible host. Tissue inflammation and hyperinnervation are characteristic findings which explain symptoms and clinical signs. Education of health care providers of LPV is important since this condition is common, often unrecognized, and patients often become frustrated users of health care. Research is needed on the antigen triggers of the syndrome. Randomized clinical trials are needed to evaluate treatment modalities.
Learn More >Neuromuscular impairments are frequently observed in patients with chronic neck pain (CNP). This study uniquely investigates whether changes in neck muscle synergies detected during gait are sensitive enough to differentiate between people with and without CNP. Surface electromyography (EMG) was recorded from the sternocleidomastoid, splenius capitis, and upper trapezius muscles bilaterally from 20 asymptomatic individuals and 20 people with CNP as they performed rectilinear and curvilinear gait. Intermuscular coherence was computed to generate the functional inter-muscle connectivity network, the topology of which is quantified based on a set of graph measures. Besides the functional network, spectrotemporal analysis of each EMG was used to form the feature set. With the use of Neighbourhood Component Analysis (NCA), we identified the most significant features and muscles for the classification/differentiation task conducted using K-Nearest Neighbourhood (K-NN), Support Vector Machine (SVM), and Linear Discriminant Analysis (LDA) algorithms. The NCA algorithm selected features from muscle network topology as one of the most relevant feature sets, which further emphasize the presence of major differences in muscle network topology between people with and without CNP. Curvilinear gait achieved the best classification performance through NCA-SVM based on only 16 features (accuracy: 85.00%, specificity: 81.81%, and sensitivity: 88.88%). Intermuscular muscle networks can be considered as a new sensitive tool for the classification of people with CNP. These findings further our understanding of how fundamental muscle networks are altered in people with CNP.
Learn More >Although there have been many magnetic resonance spectroscopy (MRS) studies of migraine, few have focused on migraines during an attack. Here, we aimed to assess metabolite changes in the brain of patients with migraine, both during an attack and in the interictal phase. Six patients (one man and five women, mean age: 39 ± 10 years) with migraine without aura during the attack (MWoA-DA), 13 patients (three men and 10 women, mean age: 31 ± 9 years) with migraine without aura during the interictal period (MWoA-DI), and 13 healthy controls (HC) (four men and nine women, mean age: 31 ± 9 years) were studied. All subjects underwent an MRS examination focusing on the occipital lobe. Metabolite changes were investigated among three groups. The MWoA-DA patients had lower glutathione/total creatine ratio (GSH/tCr) than the MWoA-DI patients and HC. Furthermore, MWoA-DI patients showed lower total choline/total creatine ratio (tCho/tCr) than those in the other two groups. The GSH/tCr ratio was positively correlated with attack frequency in the MWoA-DI group. The tCho/tCr ratio was positively correlated with attack frequency and Migraine Disability Assessment Scale (MIDAS) scores in the MWoA-DA group. The present study suggests the existence of distinct pathophysiological states between the MWoA-DA and MWoA-DI groups. Neuronal dysfunction is a possible predisposing factor for migraine attack onset, along with oxidative stress and inflammation.
Learn More >Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent hybridization. CRF antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.
Learn More >This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.
Learn More >PainData is an electronic internet-based clinical pain registry established to improve the understanding and treatment of high-impact chronic pain. The primary aim of this paper is to describe socio-demographics, pain characteristics, quality of life, and treatment values at baseline and follow-up in individuals referred to public and private interdisciplinary pain centers in Denmark between 2018 and 2020.
Learn More >The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study ( = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37-2.54]), recent suicide attempt (OR = 1.88 [1.14-3.09]), higher use of tobacco (OR = 1.05 [1.02-1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06-1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68-0.83]), escitalopram (OR = 0.75 [0.67-0.85]) and venlafaxine (OR = 0.78 [0.68-0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30-0.67]), escitalopram (OR = 0.45 [0.27-0.74]) and citalopram (OR = 0.32 [0.15-0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
Learn More >A plethora of evidence supports the existence of neuromuscular changes in people with chronic spinal pain (neck and low back pain), yet it is unclear whether neuromuscular adaptations persist for people with recurrent spinal pain when in a period of remission. This systematic review aimed to synthesise the evidence on neuromuscular adaptations in people with recurrent spinal pain during a period of remission. Electronic databases, grey literature, and key journals were searched from inception up to the 4th of September 2020. Eligibility criteria included observational studies investigating muscle activity, spine kinematics, muscle properties, sensorimotor control, and neuromuscular performance in adults (≥ 18 years) with recurrent spinal pain during a period of remission. Screening, data extraction, and quality assessment (Newcastle-Ottawa Scale) were conducted independently by two reviewers. Data synthesis was conducted per outcome domain. A meta-analysis with a random-effects model was performed where possible. The overall strength of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines (GRADE). From 8292 records, 27 and five studies were included in a qualitative and quantitative synthesis, respectively. Very low level of evidence supports muscle activity changes in people with recurrent low back pain, especially greater co-contraction, redistribution of muscle activity, and delayed postural control of deeper trunk muscles. Reduced range of motion of the lumbar spine was also found. Meaningful conclusions regarding other outcome domains or people with recurrent neck pain could not be drawn. In conclusion, people with recurrent low back pain during a period of remission show muscle activity and spine kinematics adaptations. Future research should investigate the long-term impact of these changes, as well as adaptations in people with recurrent neck pain.
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