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Papers: 2 Jul 2022 - 8 Jul 2022

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Corticostriatal circuits in the transition to chronic back pain: The predictive role of reward learning.

Connectivity between the nucleus accumbens (NAc) and ventromedial prefrontal cortex (vmPFC) and reward learning independently predict the transition from acute to chronic back pain (CBP). However, how these predictors are related remains unclear. Using functional magnetic resonance imaging, we investigate NAc- and vmPFC-dependent reward learning in 50 patients with subacute back pain (SABP) and follow them over 6 months. Additionally, we compare 29 patients with CBP and 29 pain-free controls to characterize mechanisms of reward learning in the chronic stage. We find that the learning-related updating of the value of reinforcement (prediction error) in the NAc predicts the transition to chronicity. In CBP, compared with controls, vmPFC responses to this prediction error signal are decreased, but increased during a discriminative stimulus. Distinct processes of reward learning in the vmPFC and NAc characterize the development and maintenance of CBP. These could be targeted for the prevention and treatment of chronic pain.

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A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.

Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury-induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury-induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

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Distinct nociception processing in the dysgranular and barrel regions of the mouse somatosensory cortex.

Nociception, a somatic discriminative aspect of pain, is, like touch, represented in the primary somatosensory cortex (S1), but the separation and interaction of the two modalities within S1 remain unclear. Here, we show spatially distinct tactile and nociceptive processing in the granular barrel field (BF) and adjacent dysgranular region (Dys) in mouse S1. Simultaneous recordings of the multiunit activity across subregions revealed that Dys neurons are more responsive to noxious input, whereas BF neurons prefer tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities seem to converge on individual layer 5 neurons of each region, but to a different extent. Overall, these findings show layer-specific processing of nociceptive and tactile information between Dys and BF. We further demonstrated that Dys activity, but not BF activity, is critically involved in pain-like behavior. These findings provide new insights into the role of pain processing in S1.

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Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus.

Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/µl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance.

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Galcanezumab modulates Capsaicin-induced C-fiber reactivity.

The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful.

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Age-Induced Changes in μ-Opioid Receptor Signaling in the Midbrain Periaqueductal Gray of Male and Female Rats.

Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. The present study investigated the impact of advanced age and biological sex on opioid signaling in the ventrolateral periaqueductal gray (vlPAG) in the presence of chronic inflammatory pain. Assays measuring μ-opioid receptor (MOR) radioligand binding, GTPγS binding, receptor phosphorylation, cAMP inhibition, and regulator of G-protein signaling (RGS) protein expression were performed on vlPAG tissue from adult (2-3 months) and aged (16-18 months) male and female rats. Persistent inflammatory pain was induced by intraplantar injection of complete Freund's adjuvant (CFA). Adult males exhibited the highest MOR binding potential (BP) and highest G-protein activation (activation efficiency ratio) in comparison to aged males and females (adult and aged). No impact of advanced age or sex on MOR phosphorylation state was observed. DAMGO-induced cAMP inhibition was highest in the vlPAG of adult males compared with aged males and females (adult and aged). vlPAG levels of RGS4 and RGS9-2, critical for terminating G-protein signaling, were assessed using RNAscope. Adult rats (both males and females) exhibited lower levels of vlPAG RGS4 and RGS9-2 mRNA expression compared with aged males and females. The observed age-related reductions in vlPAG MOR BP, G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in RGS4 and RGS9-2 vlPAG expression, provide potential mechanisms whereby the potency of opioids is decreased in the aged population.Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. In the present study, we observed age-related reductions in ventrolateral periaqueductal gray (vlPAG) μ-opioid receptor (MOR) binding potential (BP), G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in regulator of G-protein signaling (RGS)4 and RGS9-2 vlPAG expression, providing potential mechanisms whereby the potency of opioids is decreased in the aged population. These coordinated decreases in opioid receptor signaling may explain the previously reported reduced potency of opioids to produce pain relief in females and aged rats.

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Meclizine and metabotropic glutamate receptor agonists attenuate severe pain and Ca activity of primary sensory neurons in chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) affects about 68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca activity of the large population of DRG neurons For the latter, we used a genetically-encoded Ca indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca activity in DRG neurons, increased number of Ca transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)-3,4-DCPG, the group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)-3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted.Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persist several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Utilizing GCaMP Ca imaging in live animals over 1800 neurons/DRG at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca activity and develops various sensitization. Metabotropic glutamate receptor agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.

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Enhancement of P2X3 Receptor-Mediated Currents by Lysophosphatidic Acid in Rat Primary Sensory Neurons.

Lysophosphatidic acid (LPA), a lipid metabolite, plays a role in both neuropathic and inflammatory pain through LPA receptors. P2X3 receptor has also been shown to participate in these pathological processes. However, it is still unclear whether there is a link between LPA signaling and P2X3 receptors in pain. Herein, we show that a functional interaction between them in rat dorsal root ganglia (DRG) neurons. Pretreatment of LPA concentration-dependently enhanced α,β-methylene-ATP (α,β-meATP)-induced inward currents mediated by P2X3 receptors. LPA significantly increased the maximal current response of α,β-meATP, showing an upward shift of the concentration-response curve for α,β-meATP. The LPA enhancement was independent on the clamping-voltage. Enhancement of P2X3 receptor-mediated currents by LPA was prevented by the LPA receptor antagonist Ki16198, but not by the LPA receptor antagonist H2L5185303. The LPA-induced potentiation was also attenuated by intracellular dialysis of either G-protein inhibitor or protein kinase C (PKC) inhibitor, but not by Rho inhibitor. Moreover, LPA significantly changed the membrane potential depolarization and action potential burst induced by α,β-meATP in DRG neurons. Finally, LPA exacerbated α,β-meATP- induced nociceptive behaviors in rats. These results suggested that LPA potentiated the functional activity of P2X3 receptors in rat primary sensory neurons through activation of the LPA receptor and its downstream PKC rather than Rho signaling pathway, indicating a novel peripheral mechanism underlying the sensitization of pain.

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The Characteristics of White Matter Hyperintensities in Patients With Migraine.

The presence of white matter hyperintensities (WMHs) in migraine is well-documented, but the location of WMH in patients with migraine is insufficiently researched. This study assessed WMH in patients with migraine using a modified version of the Scheltens visual rating scale, a semiquantitative scale for categorizing WMH in periventricular, lobar, basal ganglia, and infratentorial regions.

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Etiologies and Utility of Diagnostic Tests in Trigeminal Neuropathy.

To evaluate the utility of diagnostic studies in identifying treatable etiologies of trigeminal neuropathy (TNP).

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Measurement properties and minimal important change of the World Health Organization Disability Assessment Schedule 2.0 in persons with low back pain: A systematic review.

We conducted a systematic review to determine measurement properties and minimal important change (MIC) of World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) short (12 questions) and full (36 questions) versions in persons with non-specific LBP.

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Intra-articular Treatment of Digital Osteoarthritis by Radiosynoviorthesis-Clinical Outcome in Long-term Follow-up.

This retrospective study analyzed the long-term effects of radiosynoviorthesis (RSO) with special emphasis to local joint pain in patients from 4 different RSO centers in Germany and Austria.

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Medicare Part D Coverage Restrictions and Patient Cost-Sharing for Opioids Commonly Used for Cancer Pain, 2015-2021.

Nation-wide rapid declines in prescription opioid dispensing gave rise to concerns regarding restricted access to effective pain management for patients with cancer-related pain. One important mechanism for such restrictions could be through more restrictive insurance coverage for opioids. This study aims to assess recent changes in Medicare Part D formulary designs for opioids commonly used for cancer-related pain.

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Migraine-attributed burden, impact and disability, and migraine-impacted quality of life: Expert consensus on definitions from a Delphi process.

Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health policy, requiring clear and agreed definitions. We aimed to formulate concise and precise definitions of these concepts by expert consensus.

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Sickle Cell Disease: A Review.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US.

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Cinnamoyloxy-mammeisin, a coumarin from propolis of stingless bees, attenuates Th17 cell differentiation and autoimmune inflammation via STAT3 inhibition.

T helper 17 (Th17) lymphocytes play a critical role in the pathogenesis of autoimmune diseases, mainly by producing the pro-inflammatory cytokine interleukin-17 (IL-17). Therefore, Th17 lymphocytes have been considered a strategic target for drug discovery and development. In this study, we investigated the activity and possible mechanisms of action of a 4-phenyl coumarin isolated from propolis, named cinnamoyloxy-mammeisin (CNM), in Th17 cell differentiation and the development of experimental Th17-dependent autoimmune encephalomyelitis (EAE). Our data showed that in vitro Th17 cell differentiation was attenuated by CNM treatment in a concentration-dependent manner (1, 3, and 10 μM). This was associated with a reduction in the release of IL-17 (35% inhibition) and interleukin-22 (IL-22, 51% inhibition). Th17-differentiated cells exposed to CNM also downregulated the expression of Th17 hallmarked cell genes, such as RAR-related orphan receptor c (Rorc, 51% inhibition), and interleukin-23 receptor (Il23r, 64% inhibition), indicating possible upstream molecular mechanisms. Mechanistically, CNM significantly reduced the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) during in vitro Th17 cell differentiation. In vivo treatment with CNM (100 μg/kg) reduced the clinical signs of EAE, which was associated with a reduction in Central Nervous System demyelination, neuroinflammation, and Th17 response in the spinal cord and inguinal lymph nodes. Consistent with this, CNM also effectively attenuated human Th17 differentiation in vitro. Collectively, our results highlight the potential of CNM as a new molecule that can modulate Th17 cells via inhibition of STAT3 signaling and, as a result, reduce autoimmune inflammation.

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Effect of early breast feeding on pain perception in women undergoing spinal anaesthesia for caesarean delivery: a comparative study.

Postoperative pain reduction is a key priority after caesarean delivery. Current recommendations are to breastfeed the baby as soon as possible after birth, including after caesarean section. However, analgesics can transfer into breast milk, and hence an ideal scenario is a postoperative period free from analgesics and pain. The aim of this study was to determine the effect of early breastfeeding on pain perception after caesarean delivery with spinal anaesthesia in the Gaza Strip.

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Generation of an model for peripheral neuropathy in Fabry disease using CRISPR-Cas9 in the nociceptive dorsal root ganglion cell line 50B11.

Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the lysosomal enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). As a result, the glycolipid substrate, globotriaosylceramide (Gb3) accumulates in various cell types throughout the body producing a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. A hallmark of this disorder is neuropathic pain that occurs in up to 80% of Fabry patients and has been characterized as a small fiber neuropathy. The molecular mechanism by which changes in AGA activity produce neuropathic pain is not clear, in part due to a lack of relevant model systems. Using 50B11 cells, an immortalized dorsal root ganglion neuron with nociceptive characteristics derived from rat, we used CRISPR-Cas9 gene editing of the galactosidase alpha () gene for AGA to create two stable knock-out clones that have the phenotypic characteristics of Fabry cells. The cell lines show severely reduced lysosomal AGA activity in homogenates as well as impaired degradation of Gb3 in cultured cells. This phenotype is stable over long-term culture. Similar to the unedited 50B11 cell line, the clones differentiate in response to forskolin and extend neurites. Flow cytometry experiments demonstrate that the gene-edited cells express TRPV1 pain receptor at increased levels compared to control, suggesting a possible mechanism for increased pain sensitization in Fabry patients. Our 50B11 cell lines show phenotypic characteristics of Fabry disease and grow well under standard cell culture conditions. These cell lines can provide a convenient model system to help elucidate the molecular mechanism of pain in Fabry patients.

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Intrathecal Drug Delivery: Advances and Applications in the Management of Chronic Pain Patient.

Advances in our understanding of the biology of spinal systems in organizing and defining the content of exteroceptive information upon which higher centers define the state of the organism and its role in the regulation of somatic and automatic output, defining the motor response of the organism, along with the unique biology and spatial organization of this space, have resulted in an increased focus on therapeutics targeted at this extracranial neuraxial space. Intrathecal (IT) drug delivery systems (IDDS) are well-established as an effective therapeutic approach to patients with chronic non-malignant or malignant pain and as a tool for management of patients with severe spasticity and to deliver therapeutics that address a myriad of spinal pathologies. The risk to benefit ratio of IDD makes it a useful interventional approach. While not without risks, this approach has a significant therapeutic safety margin when employed using drugs with a validated safety profile and by skilled practioners. The present review addresses current advances in our understanding of the biology and dynamics of the intrathecal space, therapeutic platforms, novel therapeutics, delivery technology, issues of safety and rational implementation of its therapy, with a particular emphasis upon the management of pain.

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Preferred Communication Strategies Used by Physical Therapists in Chronic Pain Rehabilitation: a Qualitative Systematic Review and Meta-Synthesis.

Lack of clarity regarding effective communication behaviors in chronic pain management is a barrier for implementing psychologically informed physical therapy approaches that rely on competent communication by physical therapist providers. This study aimed to conduct a systematic review and meta-synthesis to inform the development of a conceptual framework for preferred communication behaviors in pain rehabilitation.

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Notch signaling activation contributes to paclitaxel-induced neuropathic pain via activation of A1 astrocytes.

Paclitaxel-induced neuropathic pain (PINP) is a progressive and refractory side effect of chemotherapy with few effective treatments at present. It is well-established that astrocytes activation contributes to the development of PINP. Recent reports showed astrocytes can be divided into A1 and A2 phenotypes. However, whether the transformation of astrocytes participates in PINP and the underlying mechanisms remain unknown. As Notch signaling pathways have shown to be involved in neuropathic pain, we aimed to investigate the relationship between Notch signaling pathway and A1 astrocytes in PINP. Herein we found that both A1 astrocytes and Notch signaling were markedly activated in the spinal cord of PINP rats and the downstream molecules of Notch signaling were colocalized with A1 astrocytes. DAPT (an inhibitor of Notch signaling) not only suppressed the mechanical allodynia of PINP rats, but also inhibited the activation of Notch signaling pathway and A1 astrocytes. Furthermore, Jagged1 (a ligand of Notch1 receptors) dose-dependently induced mechanical hyperalgesia in naïve rats and simultaneously led to Notch signaling activation and A1 astrocytes transformation, all of which were inhibited by DAPT. Taken together, these results demonstrate Notch signaling activation contributes to PINP via A1 astrocytes activation, which provides a promising therapeutic target for PINP.

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Protocols for measuring cold-evoked neural activity and cold tolerance in Drosophila larvae following fictive cold acclimation.

Here, we outline protocols to study cold acclimation in Drosophila from a neurobiological perspective, starting with fictive cold acclimation using a custom-built optogenetics-housing apparatus we call the OptoBox. We also provide detailed steps for single-unit electrophysiological recordings from larval cold nociceptors and a high-throughput cold-tolerance assay. These protocols expand the toolkit for the study of insect cold acclimation and nociception. For complete details on the use and execution of this protocol, please refer to Himmel et al. (2021).

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Effectiveness of anti-CGRP monoclonal antibodies on central symptoms of migraine.

Clinical trials and observational studies with anti-calcitonin gene-related peptide antibodies poorly investigated their impact on migraine prodromal and accompanying symptoms. This information might help deciphering the biologics' pharmacodynamic and provide hints on migraine pathogenesis. Herein, we report the effects of erenumab, fremanezumab and galcanezumab on attack prodromal and accompanying symptoms and on neurological and psychiatric traits. .

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High-Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guidelines for the Evaluation and Diagnosis of Acute Chest Pain.

The 2021 American Heart Association/American College of Cardiology/American Society of Echocardiography/American College of Chest Physicians/Society for Academic Emergency Medicine/Society of Cardiovascular Computed Tomography/Society for Cardiovascular Magnetic Resonance guidelines for the evaluation and diagnosis of acute chest pain make important recommendations that include the recognition of high-sensitivity cardiac troponin (hs-cTn) as the preferred biomarker, endorsement of 99th percentile upper reference limits to define myocardial injury, and the use of clinical decision pathways, as well as acknowledgement of the uniqueness of women and other patient subsets. Details on how to integrate hs-cTn into clinical practice are less extensively addressed. Clinicians should be aware of some of the analytical aspects related to hs-cTn assays regarding the limit of detection and the limit of quantitation and how they are used clinically, especially for the single sample strategy to rule out acute myocardial infarction. Likewise, it is important for clinicians to understand issues related to the derivation of the 99th percentile upper reference limit; the value of sex-specific 99th percentile upper reference limits; how to use changing concentrations (deltas) to facilitate diagnosis and risk stratification of patients with suspected acute coronary syndrome, including the differentiation of acute from chronic myocardial injury; and how to best integrate the use of hs-cTn with clinical decision pathways. With the use of hs-cTn, conditions such as type 2 myocardial infarction become more common, whereas others such as unstable angina become less frequent but still occur. Sections relating to these issues are included.

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Neuroinflammation Involved in Diabetes-Related Pain and Itch.

Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.

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The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies.

Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer's disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein-biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

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Personal view: Modelling pain mechanisms of migraine without aura.

This review aims to model migraine nociception.

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New Daily Persistent Headache-A Start With an Uncertain End.

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Prioritizing Suggestive Candidate Genes in Migraine: An Opinion.

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Persistence, use of resources and costs in patients under migraine preventive treatment: the PERSEC study.

Migraine represents a serious burden for national health systems. However, preventive treatment is not optimally applied to reduce the severity and frequency of headache attacks and the related expenses. Our aim was to assess the persistence to traditional migraine prophylaxis available in Spain and its relationship with the healthcare resource use (HRU) and costs.

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Comparison of Patient-Controlled Caudal Epidural Analgesia and Patient-Controlled Intravenous Analgesia After Perianal Surgery: A Randomized Controlled Trial.

This study aimed to compare the efficacy between patient-controlled caudal epidural analgesia (PCCA) and patient-controlled intravenous analgesia (PCIA) after perianal surgery, to provide a feasible solution to postoperative pain.

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Epidemiology of persistent postoperative opioid use after cardiac surgery: a systematic review and meta-analysis.

The epidemiology of persistent postoperative opioid use at least 3 months after cardiac surgery is poorly characterised despite its potential public health importance.

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Effects of a supervised exercise program in addition to electrical stimulation or kinesio taping in low back pain: a randomized controlled trial.

Chronic low back pain it is one of the most common health problems worldwide. Usually is accompanied by a complex set of symptoms and generates significant direct and indirect socioeconomic and health costs. From a therapeutic point of view, there are a wide variety of methods to address the treatment of this pathology, however, these therapies have not been shown definitive efficacy. To investigate the effect of a mixed treatment with exercise and electrical stimulation versus exercise and kinesio taping in patients with non-specific chronic low back pain. A total of 58 patients participated in this single-blinded randomised clinical trial. Participants were assigned to the exercises- kinesio taping group, or exercises- analgesic current group, both received 12 treatment sessions. Disability, fear of movement, anxiety, depression, sleeps quality, pain, lower limb mechanosensitivity and pressure-pain thresholds were recorded at baseline and after 4 weeks of treatment. The 2 × 2 mixed analysis of covariance test showed statistically significant differences between groups for pain (P = 0.046). Pair-wise comparisons with baseline demonstrated significant differences for both groups in pain (P ≤ 0.001), disability (P ≤ 0.001), pressure-pain thresholds (P ≤ 0.044), lower limb mechanosensitivity, (P ≤ 0.047), anxiety (P ≤ 0.001), depression (P ≤ 0.001) and sleep quality (P ≤ 0.010). Patients with chronic low back pain who received a combined treatment of exercises and kinesio taping or analgesic current showed an improvement in pain, disability, anxiety, depression and sleep pattern. Moreover, exercises combined with electrotherapy produces greater improvements over these variables.Trial registration: NCT02812459.

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Neuropathic Corneal Pain as Debilitating Manifestation of LONG-COVID.

This report illustrates the case of a female patient suffering from severe ocular discomfort, tinnitus and ageusia, 7 months after a SARS-CoV-2 infection. The medical history implicated a diagnosis of LONG-COVID with ocular pain as the most debilitating symptom. In-vivo confocal microscopy revealed corneal microneuromas with hyperreflectivity and irregular enlargement of nerve endings in both eyes, which led to the diagnosis of neuropathic corneal pain. The aim of this report is to increase awareness that COVID-19 induced neuropathic pain can also occur in the cornea representing the human body's most richly innervated tissue.

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Acute Perioperative Pain Management Among Adult Patients Undergoing Orthopaedic Surgery.

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Validation of the German version of the STarT-MSK-Tool: A cohort study with patients from physiotherapy clinics.

The STarT-MSK-Tool is an adaptation of the well established STarT-Back-Tool, used to risk-stratify patients with a wider range of musculoskeletal presentations.

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Early Onset Diffusion Abnormalities in Refractory Headache Disorders.

This study sought to determine if individuals with medically refractory migraine headache have volume or diffusion abnormalities on neuroimaging compared to neurotypical individuals.

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Basivertebral Nerve Ablation for the Treatment of Chronic Low Back Pain: A Scoping Review of the Literature.

Chronic low back pain is a leading cause of disability worldwide and its pathophysiology remains poorly understood, a problem exacerbated by the heterogeneity of the patient population with chronic low back pain. Although the intervertebral discs are often implicated in chronic low back pain, studies have demonstrated strong innervation of the vertebral endplates by the basivertebral nerve, therefore making it a possible target for ablation in the treatment of vertebrogenic chronic low back pain.

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The Role of Neuromodulation in Chronic Pelvic Pain: A Review Article.

Chronic pelvic pain (CPP) is a complex, heterogeneous condition affecting both female and male patients with significant effects on quality of life. Chronic pelvic pain is a prevalent but often underdiagnosed condition due to the variation in patient presentation, a gap in communication among specialties, under-reporting of the syndrome, and lack of standardized diagnostic criteria with a subsequent delay in diagnosis. The mechanism of CPP is complex due to multifactorial etiologies of pain and its vast anatomy and innervation. Potential causes of pelvic pain include the nerves, muscles, bone, or organs of the reproductive, gastrointestinal, urological, musculoskeletal, vascular, neurological, and psychological systems.

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Involvement of nerve growth factor (NGF) in chronic neuropathic pain – a systematic review.

Pain is a complex experience, encompassing physiological and psychological components. Amongst the different types of pain, neuropathic pain, resulting from injuries to the peripheral or central nervous system, still constitutes a challenge for researchers and clinicians. Nerve growth factor (NGF) is currently regarded as a key contributor and may serve as a therapeutic target in many types of pain, likely including neuropathic pain. Here, we reviewed the role of NGF in neuropathic pain of peripheral and central origin, also addressing its potential use as a pharmacological target to better help patients dealing with this condition that severely impacts the everyday life. For this, we conducted a search in the databases PubMed and Scopus. Our search resulted in 1103 articles (458 in PubMed and 645 in Scopus). Only articles related to the involvement of NGF in pain or articles that approached its potential use as a target in treatment of pain symptoms were included. Duplicates were eliminated and 274 articles were excluded. After careful analysis, 23 articles were selected for review. Original articles studying the role of NGF in pathology as well as its modulation as a possible therapeutic target were included. We found that NGF is widely regarded as a key player in neuropathic pain and seen as a putative therapeutic target. However, evidence obtained from years of clinical trials highlights the toxic adverse effects of anti-NGF therapeutics, precluding its use in clinical context. Further studies are, thus, needed to improve treatment of chronic neuropathic pain.

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Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study.

Osteoarthritis can have a profound effect on patients' quality of life. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study aimed to describe the impact of osteoarthritis on quality of life and determine the association with factors such as pain severity and pharmacological treatment.

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Clinical factors and pre-surgical depression scores predict pain intensity in cardiac surgery patients.

Severe pain is prevalent in cardiac surgery patients and can increase cardiac complications, morbidity and mortality. The objectives of the study were to assess perioperative pain intensity and to assess predictors of pain post-cardiac surgery, including clinical characteristics and depression.

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ATRPred: A machine learning based tool for clinical decision making of anti-TNF treatment in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic autoimmune condition, characterised by joint pain, damage and disability, which can be addressed in a high proportion of patients by timely use of targeted biologic treatments. However, the patients, non-responsive to the treatments often suffer from refractoriness of the disease, leading to poor quality of life. Additionally, the biologic treatments are expensive. We obtained plasma samples from N = 144 participants with RA, who were about to commence anti-tumour necrosis factor (anti-TNF) therapy. These samples were sent to Olink Proteomics, Uppsala, Sweden, where proximity extension assays of 4 panels, containing 92 proteins each, were performed. A total of n = 89 samples of patients passed the quality control. The preliminary analysis of plasma protein expression values suggested that the RA population could be divided into two distinct molecular sub-groups (endotypes). However, these broad groups did not predict response to anti-TNF treatment, but were significantly different in terms of gender and their disease activity. We then labelled these patients as responders (n = 60) and non-responders (n = 29) based on the change in disease activity score (DAS) after 6 months of anti-TNF treatment and applied machine learning (ML) with a rigorous 5-fold nested cross-validation scheme to filter 17 proteins that were significantly associated with the treatment response. We have developed a ML based classifier ATRPred (anti-TNF treatment response predictor), which can predict anti-TNF treatment response in RA patients with 81% accuracy, 75% sensitivity and 86% specificity. ATRPred may aid clinicians to direct anti-TNF therapy to patients most likely to receive benefit, thus save cost as well as prevent non-responsive patients from refractory consequences. ATRPred is implemented in R.

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Telemedicine in headache care: A systematic review.

Telemedicine is defined as video-based consultations with synchronous video and sound. This systematic review investigated the use of telemedicine for headache patients. The primary outcomes of interest were treatment efficacy, feasibility, safety, convenience, compliance, and patient satisfaction.

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A Progress Report and Roadmap for Microphysiological Systems and Organ-On-A-Chip Technologies to Be More Predictive Models in Human (Knee) Osteoarthritis.

Osteoarthritis (OA), a chronic debilitating joint disease affecting hundreds of million people globally, is associated with significant pain and socioeconomic costs. Current treatment modalities are palliative and unable to stop the progressive degeneration of articular cartilage in OA. Scientific attention has shifted from the historical view of OA as a wear-and-tear cartilage disorder to its recognition as a whole-joint disease, highlighting the contribution of other knee joint tissues in OA pathogenesis. Despite much progress in the field of microfluidic systems/organs-on-a-chip in other research fields, current models in use do not yet accurately reflect the complexity of the OA pathophenotype. In this review, we provide: 1) a detailed overview of the most significant recent developments in the field of microsystems approaches for OA modeling, and 2) an OA-pathophysiology-based bioengineering roadmap for the requirements of the next generation of more predictive and authentic microscale systems fit for the purpose of not only disease modeling but also of drug screening to potentially allow OA animal model reduction and replacement in the near future.

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Molecular Determinants of Mechanical Itch Sensitization in Chronic Itch.

Chronic itch is associated with sensitization of the somatosensory nervous system. Recent studies have identified the neural circuits transmitting acute itch; however, the mechanisms by which itch transforms into a pathological state remain largely unknown. We have previously shown that Aβ low-threshold mechanoreceptors, together with spinal urocortin 3-positive (Ucn3) excitatory interneurons and neuropeptide Y-positive (NPY) inhibitory interneurons, form a microcircuit that transmits and gates acute mechanical itch. Here, using whole-cell patch-clamp recordings, we observed increased excitability in spinal Ucn3 neurons under chronic itch conditions. In contrast to Ucn3 neurons, the excitability of spinal NPY neurons was largely reduced under chronic itch conditions. To explore the molecular mechanisms underlying sensitization of this microcircuit, we examined the mRNA expression levels of voltage-gated ion channels in recorded spinal Ucn3 and NPY neurons by single-cell quantitative real-time PCR (qRT-PCR). We found that the expression levels of Nav1.6 and Cav2.3 channels were increased in spinal Ucn3 neurons in chronic itch mice, while the expression level of SK3 channels was decreased. By contrast, the expression levels of Nav1.6 and BK channels were decreased in spinal NPY neurons in chronic itch mice. To determine the contribution of different ion channels in chronic itch sensitization, we then used a Markov Chain Monte Carlo method to parameterize a large number of biophysically distinct multicompartment models of Ucn3 and NPY neurons. These models included explicit representations of the ion channels that we found to be up- or down-regulated under chronic itch conditions. Our models demonstrated that changes in Nav1.6 conductance are predominantly responsible for the changes in excitability of both Ucn3 and NPY neurons during chronic itch pathogenesis. Furthermore, when simulating microcircuits of our Ucn3 and NPY models, we found that reduced Nav1.6 conductance in NPY models played a major role in opening the itch gate under chronic itch conditions. However, changing SK, BK, or R-type calcium channel conductance had negligible effects on the sensitization of this circuit. Therefore, our results suggest that Nav1.6 channels may play an essential role in mechanical itch sensitization. The findings presented here may open a new avenue for developing pharmaceutical strategies to treat chronic itch.

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Next generation behavioral sequencing for advancing pain quantification.

With symptoms such as spontaneous pain and pathologically heightened sensitivity to stimuli, chronic pain accounts for about 20% of physician visits and up to 2/3 of patients are dissatisfied with current treatments. Much of our knowledge on pain processing and analgesics has emerged from behavioral studies performed on animals presenting the same symptoms under pathological conditions. While humans can verbally describe their pain, studies on rodents have relied on behavioral assays providing non-exhaustive characterization or altering animals' original sensitivity through repetitive stimulations. The emergence of what we term "next-generation behavioral sequencing" is now permitting us to quantitatively describe behavioral features on millisecond to minutes long timescales that lie beyond easy detection with the unaided eye. Here, we summarize emerging videography and computational based behavioral approaches that have the potential to significantly improve pain research.

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Decoding gene expression signatures in mice trigeminal ganglion across trigeminal neuropathic pain stages via high-throughput sequencing.

Trigeminal neuropathic pain (TNP) arises due to peripheral nerve injury, the mechanisms underlying which are little known. The altered gene expression profile in sensory ganglia is critical for neuropathic pain generation and maintenance. We, therefore, assessed the transcriptome of the trigeminal ganglion (TG) from mice at different periods of pain progression. Trigeminal neuropathic pain was established by partial infraorbital nerve transection (pIONT). High-throughput RNA sequencing was applied to detect the mRNA profiles of TG collected at 3 and 10 days after modeling. Injured TG displayed dramatically altered mRNA expression profiles compared to Sham. Different gene expression profiles were obtained at 3 and 10 days after pIONT. Moreover, 314 genes were significantly upregulated, and 81 were significantly downregulated at both 3 and 10 days post-pIONT. Meanwhile, enrichment analysis of these persistent differentially expressed genes (DEGs) showed that the MAPK pathway was the most significantly enriched pathway for upregulated DEGs, validated by immunostaining. In addition, TG cell populations defined by single-nuclei RNA sequencing displayed cellular localization of DEGs at a single-cell resolution. Protein-protein interaction (PPI) and sub-PPI network analyses constructed networks and identified the top 10 hub genes for DEGs at different time points. The present data provide novel information on the gene expression signatures of TG during the development and maintenance phases of TNP, and the identified hub genes and pathways may serve as potential targets for treatment.

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IL-10 alleviates radicular pain by inhibiting TNF-α/p65 dependent Nav1.7 up-regulation in DRG neurons of rats.

Lumbar disc herniation (LDH) may induce radicular pain, the upregulation of voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) contributes to radicular pain by generating ectopic discharge of neurons, but the mechanism is unclear. Previously, we reported pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) up-regulated VGSCs in diabetic neuropathy. In this study, we explored the effect of anti-inflammatory cytokine interleukin-10 (IL-10) on radicular pain and the possible mechanisms.

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P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine.

Migraine is the second most common form of headache disorder and the second leading cause of disability worldwide. Cognitive symptoms ranked second resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved in hyperalgesia in migraine. However, the role of P2X7R in migraine-related cognitive impairment is still ill-defined. The aim of this study was to explore the molecular mechanisms underlying migraine-related cognitive impairment and the role of P2X7R in it. Here we used a well-established mouse model of migraine that triggered migraine attacks by application of inflammatory soup (IS) to the dura. Our results showed that repeated dural IS stimulation triggered upregulation of P2X7R, activation of NLRP3 inflammasome, release of proinflammatory cytokines (IL-1β and IL-18) and activation of pyroptotic cell death pathway. Gliosis (microgliosis and astrogliosis), neuronal loss and cognitive impairment also occurred in the IS-induced migraine model. No significant apoptosis or whiter matter damage was observed following IS-induced migraine attacks. These pathological changes occurred mainly in the cerebral cortex and to a less extent in the hippocampus, all of which can be prevented by pretreatment with a specific P2X7R antagonist Brilliant Blue G (BBG). Moreover, BBG can alleviate cognitive impairment following dural IS stimulation. These results identified P2X7R as a key contributor to migraine-related cognitive impairment and may represent a potential therapeutic target for mitigating cognitive impairment in migraine.

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Design, synthesis and evaluation of alpha lipoic acid derivatives to treat multiple sclerosis-associated central neuropathic pain.

Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability.

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The Association Between the Occurrence of Common Treatment-Emergent Adverse Events and Efficacy Outcomes After Lasmiditan Treatment of a Single Migraine Attack: Secondary Analyses from Four Pooled Randomized Clinical Trials.

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).

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Anti-Inflammatory Properties of KLS-13019: a Novel GPR55 Antagonist for Dorsal Root Ganglion and Hippocampal Cultures.

KLS-13019, a novel devised cannabinoid-like compound, was explored for anti-inflammatory actions in dorsal root ganglion cultures relevant to chemotherapy-induced peripheral neuropathy (CIPN). Time course studies with 3 µM paclitaxel indicated > 1.9-fold increases in immunoreactive (IR) area for cell body GPR55 after 30 min as determined by high content imaging. To test for reversibility of paclitaxel-induced increases in GPR55, cultures were treated for 8 h with paclitaxel alone and then a dose response to KLS-13019 added for another 16 h. This "reversal" paradigm indicated established increases in cell body GPR55 IR areas were decreased back to control levels. Because GPR55 had previously reported inflammatory actions, IL-1β and NLRP3 (inflammasome-3 marker) were also measured in the "reversal" paradigm. Significant increases in all inflammatory markers were produced after 8 h of paclitaxel treatment alone that were reversed to control levels with KLS-13019 treatment. Accompanying studies using alamar blue indicated that decreased cellular viability produced by paclitaxel treatment was reverted back to control levels by KLS-13019. Similar studies conducted with lysophosphatidylinositol (GPR55 agonist) in DRG or hippocampal cultures demonstrated significant increases in neuritic GPR55, NLRP3 and IL-1β areas that were reversed to control levels with KLS-13019 treatment. Studies with a human GPR55-β-arrestin assay in Discover X cells indicated that KLS-13019 was an antagonist without agonist activity. These studies indicated that KLS-13019 has anti-inflammatory properties mediated through GPR55 antagonist actions. Together with previous studies, KLS-13019 is a potent neuroprotective, anti-inflammatory cannabinoid with therapeutic potential for high efficacy treatment of neuropathic pain.

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Childhood Adversity among Adults with Chronic Pain: Prevalence and Association with Pain-Related Outcomes.

Adverse childhood experiences (ACEs) have been linked to the development and impact of chronic pain in adulthood. The goal of this study was to investigate the prevalence of ACEs in a treatment-seeking sample of adults with chronic pain and the relationship between number and type(s) of ACEs and pain-related outcomes.

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The headache registry of the German Migraine and Headache Society (DMKG): baseline data of the first 1,351 patients.

Although good treatment options exist for many headache disorders, not all patients benefit and disability continues to be large. To design strategies for improving headache care, real-world data observing standard care is necessary. Therefore, the German Migraine and Headache Society (DMKG) has established the DMKG Headache Registry. Here we present methods and baseline data.

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Neurological pain relief interventional radiology procedures.

Neurological interventions have taken on a significant role in interventional radiology (IR) practice. Indications fall under three main categories: (1) intraprocedural pain management, (2) cancer pain palliation, and (3) chronic non-cancer pain control. Short-term regional anaesthesia can be achieved with local anaesthetics, while longer-term pain control can be attained with radiofrequency neuromodulation (pulsed or otherwise) or thermal/chemical neurolysis. This review article summarises the therapeutic options, applications, and techniques of commonly used peripheral nerve and plexus interventions in IR.

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Spatial distribution of fat infiltration within the paraspinal muscles: implications for chronic low back pain.

Fat infiltration (FI) of the paraspinal muscles (PSMs) measured using MRI is an aspect of muscle quality and is considered to be worse in chronic low back pain (cLBP) patients. However, there is not a clear association between paraspinal muscle FI and cLBP, leaving the clinical importance of paraspinal muscle composition unestablished. The spatial distribution of FI in the PSMs may inform mechanistic understanding of non-specific cLBP as it relates to degenerative intervertebral disc (IVD) pathology. We hypothesized that paraspinal muscle fat-mapping would reveal distinct FI distribution patterns in relation to cLBP symptoms and proximity to symptomatic IVD degeneration.

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Radiofrequency Neurotomy does not cause fatty degeneration of the lumbar paraspinal musculature in patients with chronic lumbar pain-a retrospective 3D-computer-assisted MRI analysis using iSix software.

The present study aimed 1) to analyze the relative paraspinal autochthonous intramuscular fat volume before and after radiofrequency neurotomy (RFN), and 2) to compare it to the contralateral non-treated side.

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Characteristics of People Seeking Prescribed Cannabinoids for the Treatment of Chronic Pain: Evidence From Project Twenty 21.

Prescribed cannabinoids are now legal in the UK and increasingly being used for a variety of conditions, with one of the most frequent conditions being chronic pain. This paper describes the characteristics of individuals seeking prescribed cannabinoids for the treatment of chronic pain in Project Twenty 21, a UK based real world data registry of prescribed cannabis patients.

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Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase-1/GSDMD induced signalling.

The specific adenosine A3 receptor (A3AR) agonist (CF101) has potential for inflammation and pain in various disease, such as arthritis, cancer and neuropathic pain, while the role of A3AR in post-traumatic OA and the underlying mechanism is largely unknown. CF101 was orally administrated in OA rats induced by anterior cruciate ligament transection (ACLT) surgery, and the rat primary chondrocytes were stimulated by hydrogen peroxide (H O , 300 μM). Histologic grading system was performed for detecting cartilage degeneration and immunohistochemistry for determining pyroptosis. The moleculars associated with cartilage homeostasis and inflammatory cytokines were analysed; moreover, the activation of NLRP3 inflammasome was determined. CF101 treatment significantly attenuated OA cartilage damage, OA-related pain and cartilage pyroptosis. Chondrocytes stimulated by H O evoked ROS release, thereby promoting the activation of NLRP3 inflammasome and facilitating the cleavage of GSDMD, which ultimately resulted in the mass release of pro-inflammatory cytokines including IL-1β and IL-18, and production of matrix hydrolase. The pre-treatment with CF101 powerfully inhibited the above process both in vivo and in vitro. Our findings demonstrated that activation of A3AR attenuates OA progression and relieves pain perception through suppression of cartilage degradation and inhibition of ROS/NLRP3/GSDMD signalling, indicating pyroptosis is a potential candidate for OA treatment.

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Systematic Review of Pre-injury Migraines as a Vulnerability Factor for Worse Outcome Following Sport-Related Concussion.

Individuals with migraine disorders may be affected differently by concussions compared to individuals without migraine disorders. Prior studies on this topic have had mixed results. The purpose of this study was to systematically examine clinical outcomes following a sport-related concussion in athletes who have a pre-injury history of migraines.

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Activity limitation and participation restriction in Osteoarthritis and Rheumatoid arthritis: findings based on the National Health and Nutritional Examination Survey.

Osteoarthritis (OA) and Rheumatoid arthritis (RA) are the most common joint diseases leading to chronic pain and disability. Given the chronicity and disabling nature of OA and RA, they are likely to influence full participation of individuals in the society. An activity limitation occurs when a person has difficulty executing an activity; a participation restriction is experienced when a person has difficulty participating in a real-life situation. The aim of this study was to examine the associations between OA and RA and the domains of activity limitation and participation restriction.

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Burden of tension-type headache in the Middle East and North Africa region, 1990-2019.

Tension-type headache (TTH) is the most prevalent neurological disorder. As there is a gap in the literature regarding the disease burden attributable to TTH in the Middle East and North Africa (MENA) region, the aim of the present study was to report the epidemiological indicators of TTH in MENA, from 1990 to 2019, by sex, age and socio-demographic index (SDI).

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Vertigo, pediatric migraine, and best treatment.

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Fibromyalgia and chronic pain: are we asking about (and auditing) psychological trauma or traumatic events?

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Cognitive behaviour therapy in adults with spinal cord injury: A scoping review.

The aim of this study is to report on the extent and range of the research evaluating cognitive behaviour therapy (CBT) in adults with spinal cord injury.

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Managing fibromyalgia with complementary and alternative medical exercise: a systematic review and meta-analysis of clinical trials.

Fibromyalgia is a chronic medical condition of unclear etiopathology that diminished patients' quality of life; chronic pain is the main symptom, yet patients with fibromyalgia struggle also with depression, anxiety, and insomnia. For many years, pharmaceutical management of pain was the mainstay of treatment. In the latest decade, conventional low-impact aerobic exercise and complementary and alternative medical (CAM) exercise have become important when structuring a personalized therapeutic plan, since side effects are practically inexistent. Heterogenous studies with different methodological approaches have failed to display a clear clinical effect. We conducted a systematic review with meta-analysis of clinical trials putting emphasis on standardized measurable outcomes (Fibromyalgia Impact Questionnaire, FIQ) in our effort to draw a safe conclusion on CAM exercise's effect. After analyzing 14 studies, including 886 patients, meta analysis showed CAM exercise had a beneficial effect on patients' FIQ score reports: standardized mean difference (SMD) 1.330 (95% CI 0.733-1.928). Among them, dance and Tai chi, had a more profound effect: SMD 1.969 (95% CI 0.575-3.364) and SMD 1.852 (95% CI 0.119-3.584), respectively. However, the risk of bias was overall medium to high and statistical heterogeneity was very high. Our meta-regression analysis failed to identify any variable that could account for high heterogeneity. Even though more experimental studies should be done on this subject, CAM exercise seems beneficial for patients with Fibromyalgia.

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Association of Amount of Weight Lost After Bariatric Surgery With Intracranial Pressure in Women With Idiopathic Intracranial Hypertension.

The idiopathic intracranial hypertension randomized controlled weight trial (IIH:WT) established that weight loss through bariatric surgery significantly reduced intracranial pressure compared to a community weight management intervention. This sub-study aimed to evaluate the amount of weight loss required to reduce intracranial pressure and to explore the impact of the different bariatric surgical approaches.

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Gamma Knife Radiosurgery for Trigeminal Neuralgia : Review and Update.

Accurate diagnosis of trigeminal neuralgia (TN) is the starting point for optimal treatment. Gamma knife radiosurgery (GKRS) is currently regarded as one of the first-line treatment options for medically refractory TN. GKRS is a less invasive treatment with a low risk of complications than other surgical procedures that provides a favorable pain control (BNI I-IIIb) rate of > 75 % at short-term follow-up. Drawbacks of GKRS include the latency period before pain relief and higher recurrence rate compared with microvascular decompression. Therefore, repeat treatment is necessary if the initial GKRS was effective but followed by recurrence. The concept of dose rate and the biologically effective dose of radiation has been actively studied in radiation oncology and is also applied in GKRS for TN to achieve high safety and efficacy by prescribing the optimal dose. Recent progress in functional imaging, such as diffusion tensor imaging, enables us to understand the pathophysiology of TN and predict the clinical outcome after GKRS. Here, we review TN, GKRS, and recent updates, especially in the concepts of radiation dose, diffusion tensor imaging studies, and repeat treatment in GKRS for TN.

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Participation of Potential Transient Receptors in the Antinociceptive Effect of Pharmacopuncture.

Despite the widespread clinical use of acupuncture in painful situations, the use of this treatment should be further clarified. Nociception is mediated by the activation of nociceptors, such as transient receptor potentials (TRPs). The family of TRPs includes TRPV1, TRPM8, and TRPA1, which can be stimulated by substances such as capsaicin, menthol, and methyl salicylate, respectively.

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Efficacy and safety of low dose oral ketamine for controlling pain and distress during intravenous cannulation in children: a double-blind, randomized, placebo-controlled trial.

Ketamine is widely used in infants and young children for procedural sedation and anesthesia. The aim of this study was to evaluate the efficacy and safety of low dose oral ketamine to control pain and distress in children during intravenous (IV) cannulation.

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Trends in opioid dispensing after common abdominal and orthopedic surgery procedures in British Columbia: a retrospective cohort analysis.

Postdischarge opioid prescriptions are reportedly much higher in Canada than in other countries. To assess potentially contributing factors, we examined trends after abdominal and orthopedic surgeries in British Columbia (BC).

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Heart Rate Variability biofeedback therapy for children and adolescents with chronic pain: A pilot study.

As a brief, noninvasive, cost-effective, and technology-driven therapy, biofeedback is a promising and welcomed clinical intervention for children and adolescents with pediatric chronic pain conditions. The aim of this pilot study was to explore the application of a brief Heart Rate Variability (HRV) biofeedback intervention supplemented by at-home breathing practice as a tool for reducing symptomatology associated with chronic pain in a pediatric urban hospital setting.

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Feasibility, Usability and Implementation Context of an Internet-Based Pain Education and Exercise Program for Chronic Musculoskeletal Pain: a pilot trial of the REABILITADOR program.

Internet-based self-management programs and telerehabilitation initiatives have grown with the development of new technologies and have been extensively used for delivering healthcare in many areas. These programs overcome common barriers that patients face with traditional face-to-face healthcare, such as travel, lack of time, and high demand on the public health system. In the past years, during the emergence of the COVID-19 pandemic, this mode of delivery has become more popular. However, there is still a lack of studies testing this mode of delivery in low- and middle-income countries. To gain a better understanding of the context, feasibility and factors involved in the implementation of an online program, pilot and implementation studies are necessary. These studies can better inform whether a strategy is feasible, acceptable and adequate for its purposes and optimising resource allocation.

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Health coaching for low back pain, hip and knee osteoarthritis: A Systematic Review with Meta-Analysis.

Health coaching aims to empower people to reach their goals and is increasingly used in healthcare settings. Whether health coaching improves pain and disability for people with hip and/or knee osteoarthritis (OA), or low back pain (LBP) is yet unknown.

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Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.

The pro-inflammatory cytokine TNFα is elevated in GI disease and sensitises colonic afferents via modulation of TRPA1 and Na 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα mediated colonic afferent sensitisation. Specifically, we show that: TNFα sensitises sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitisation of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitisation of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively this data supports the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in GI disease.

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