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To develop and validate a diagnostic prediction model that can distinguish between juvenile idiopathic arthritis (JIA) and chronic musculoskeletal pain syndromes (CMPS based on patient-reported outcomes.
Learn More >Social touch-the affiliative skin-to-skin contact between individuals-can rapidly evoke emotions of comfort, pleasure, or calm, and is essential for mental and physical well-being. Physical isolation from social support can be devastating. During the COVID-19 pandemic, we observed a global increase in suicidal ideation, anxiety, domestic violence, and worsening of pre-existing physical conditions, alerting society to our need to understand the neurobiology of social touch and how it promotes normal health. Gaining a mechanistic understanding of how sensory neuron stimulation induces pleasure, calm, and analgesia may reveal untapped therapeutic targets in the periphery for treatment of anxiety and depression, as well as social disorders and traumas in which social touch becomes aversive. Bridging the gap between stimulation in the skin and positive affect in the brain-especially during naturally occurring social touch behaviors-remains a challenge to the field. However, with advances in mouse genetics, behavioral quantification, and brain imaging approaches to measure neuronal firing and neurochemical release, completing this mechanistic picture may be on the horizon. Here, we summarize some exciting new findings about social touch in mammals, emphasizing both the peripheral and central nervous systems, with attempts to bridge the gap between external stimulation and internal representations in the brain.
Learn More >PTEN is known as a tumor suppressor and plays essential roles in brain development. Here, we report that PTEN in primary sensory neurons is involved in processing itch and thermal information in adult mice. Deletion of PTEN in the dorsal root ganglia (DRG) is achieved in adult Drg11-Cre: PTEN (PTEN CKO) mice with oral administration of tamoxifen, and CKO mice develop pathological itch and elevated itch responses on exposure to various pruritogens. PTEN deletion leads to ectopic expression of TRPV1 and MrgprA3 in IB4 non-peptidergic DRG neurons, and the TRPV1 is responsive to capsaicin. Importantly, the elevated itch responses are no longer present in Drg11-Cre: PTEN: TRPV1 (PTEN: TRPV1 dCKO) mice. In addition, thermal stimulation is enhanced in PTEN CKO mice but blunted in dCKO mice. PTEN-involved regulation of itch-related gene expression in DRG neurons provides insights for understanding molecular mechanism of itch and thermal sensation at the spinal level.
Learn More >Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.
Learn More >Chronic postsurgical pain (CPSP) is defined by pain intensity and pain-related functional interference. This study included measures of function in a composite score of patient-reported outcomes (PROs) to investigate the incidence of CPSP. Registry data were analyzed for PROs one day and 12 months postoperatively. Based on pain intensity and pain-related interference with function, patients were allocated to the groups "CPSPF" (at least moderate pain with interference), "Mixed" (milder symptoms) and "No CPSPF". The incidence of CPSPF was compared to CPSP rates referring to published data. Variables associated with the PRO-12 score (composite PROs at 12 months; NRS 0-10) were analyzed by linear regression analysis. Of 2319 patients, 8.6%, 32.5% and 58.9% were allocated to the groups CPSPF, Mixed and No CPSPF. Exclusion of patients whose pain scores did not increase compared to the preoperative status, resulted in a 3.3% incidence. Of the patients without pre-existing pain, 4.1% had CPSPF. Previously published pain cut-offs of NRS >0, ≥3 or ≥4, used to define CPSP, produced rates of 37.5%, 9.7% and 5.7%. Pre-existing chronic pain, pre-operative opioid medication and type of surgery were associated with the PRO-12 score (all p<0.05). Opioid doses and PROs 24 hours postoperatively improved the fit of the regression model. A more comprehensive assessment of pain and interference resulted in lower CPSP rates than previously reported. Although inclusion of CPSP in the ICD-11 is a welcome step, evaluation of pain characteristics would be helpful in differentiation between CPSPF and continuation of pre-existing chronic pain.
Learn More >Pyramidal cell spike block is a common occurrence in migraine with aura and epileptic seizures. In both cases, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that temporarily terminates neuronal activity. In cortical spreading depression (CSD), spike block propagates as a slowly traveling wave of inactivity through cortical pyramidal cells, which is thought to precede migraine attacks with aura. In seizures, highly synchronized cortical activity can be interspersed with, or terminated by, spike block. While the identifying characteristic of CSD and seizures is the pyramidal cell hyperexcitation, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of hyperexcitation and subsequent spike block.We tested the contribution of cortical inhibitory interneurons to the initiation of spike block using a cortical microcircuit model that takes into account changes in ion concentrations that result from neuronal firing. Our results show that interneuronal inhibition provides a wider dynamic range to the circuit and generally improves stability against spike block. Despite these beneficial effects, strong interneuronal firing contributed to rapidly changing extracellular ion concentrations, which facilitated hyperexcitation and led to spike block first in the interneuron and then in the pyramidal cell. In all cases, a loss of interneuronal firing triggered pyramidal cell spike block. However, preventing interneuronal spike block was insufficient to rescue the pyramidal cell from spike block. Our data thus demonstrate that while the role of interneurons in cortical microcircuits is complex, they are critical to the initiation of pyramidal cell spike block. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit and their contribution to CSD and epileptic seizures.
Learn More >Intervertebral disc degeneration (IVDD) is a main cause of low back pain, and inflammatory factors play key roles in its pathogenesis. Gremlin-1 (Grem1) was reported to induce an inflammatory response in other fields. This study aimed to investigate the mechanisms of Grem1 in the degenerative process of intervertebral discs. Dysregulated genes were determined by analyzing microarray profiles. The expression of Grem1 in 17 human disc samples (male:female = 9:8) and rat models (n = 5 each group) was measured by western blotting (WB), real-time quantitative PCR (RT-qPCR), and immunohistochemistry (IHC). The regulatory effects of Grem1 on apoptosis were examined using siRNAs, flow cytometry, immunofluorescence (IF), and WB. The therapeutic effect was evaluated by locally injecting specific Grem1 siRNA into IVDD rats. The expression of Grem1 was significantly increased in human degenerative intervertebral discs; furthermore, the expression of Grem1 positively correlated with the level of intervertebral disc degeneration. Grem1 was significantly overexpressed in tumor necrosis factor (TNF)-α-induced degenerative NP cells. Apoptosis in degenerative NP cells transfected with siRNA targeting Grem1 was significantly lower than that in the control group. Specific Grem1 siRNA markedly repressed the development of IVDD in surgery-induced IVDD rats. These results indicated that the expression of Grem1 was positively correlated with the severity of intervertebral disc degeneration, and Grem1 siRNA could inhibit Grem1-induced apoptosis and extracellular matrix alterations by mediating the TGF-β/Smad signaling pathway. This study may provide a therapeutic strategy for alleviating inflammation-induced apoptosis associated with intervertebral disc degeneration.
Learn More >Empirical data on the health impacts of the COVID-19 pandemic remain scarce, especially among patients with chronic pain. We conducted a cross-sectional study matched by season to examine patient-reported health symptoms among patients with chronic pain pre- and post-COVID-19 pandemic onset. Survey responses were analyzed from 7535 patients during their initial visit at a tertiary pain clinic between April 2017-October 2020. Surveys included measures of pain and pain-related physical, emotional, and social function. The post-COVID-19 onset cohort included 1798 initial evaluations, and the control pre-COVID-19 cohort included 5737 initial evaluations. Patients were majority female, White/Caucasian, and middle-aged. The results indicated that pain ratings remained unchanged among patients after the pandemic onset. However, pain catastrophizing scores were elevated when COVID-19 cases peaked in July 2020. Pain interference, physical function, sleep impairment, and emotional support were improved in the post-COVID-19 cohort. Depression, anxiety, anger, and social isolation remained unchanged. Our findings provide evidence of encouraging resilience among patients seeking treatment for pain conditions in the face of the COVID-19 pandemic. However, our findings that pain catastrophizing increased when COVID-19 cases peaked in July 2020 suggests that future monitoring and consideration of the impacts of the pandemic on patients' pain is warranted.
Learn More >Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. While the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in the majority of those who suffer. Most notable among the changes in primary afferents is an increase in excitability, or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pro-nociceptive signaling molecules such as voltage-gated sodium channels, as well as decreases in anti-nociceptive signaling molecules such as voltage- or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules appear to reflect changes in gene expression as well as post-translational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process is not only dynamically regulated, but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology.
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