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To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies.
Learn More >Given the substantial impact of herpes zoster on health and quality of life, and its considerable economic burden, prevention through vaccination is a priority. We aimed to evaluate the effectiveness of the herpes zoster vaccines (recombinant zoster vaccine [RZV] and zoster vaccine live [ZVL]) against incident herpes zoster and postherpetic neuralgia in older adults.
Learn More >Synaptic modulation and plasticity are key mechanisms underlying pain transmission in the spinal cord and supra-spinal centers. The study and understanding of these phenomena are fundamental to investigating both acute nociception and maladaptive changes occurring in chronic pain. This article describes experimental protocols and analytical methods utilized in electrophysiological studies to investigate synaptic modulation and plasticity at the first station of somatosensory processing, the spinal cord dorsal horn. Protocols useful for characterizing the nature of synaptic inputs, the site of modulation (pre- versus postsynaptic), and the presence of short-term synaptic plasticity are presented. These methods can be employed to study the physiology of acute nociception, the pathological mechanisms of persistent inflammatory and neuropathic pain, and the pharmacology of receptors and channels involved in pain transmission. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Spinal cord dissection and acute slice preparation Basic Protocol 2: Stimulation of the dorsal root and extracellular recording (compound action potentials and field potentials) Basic Protocol 3: Patch-clamp recording from dorsal horn neurons: action potential firing patterns and evoked synaptic inputs Basic Protocol 4: Analysis of parameters responsible for changes in synaptic efficacy Basic Protocol 5: Recording and analysis of currents mediated by astrocytic glutamate.
Learn More >Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies.
Learn More >Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund's adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10 days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.
Learn More >Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis (PTOA). Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant.
Learn More >An emergent subgroup of spinal cord microglia mediates recovery from persistent pain.
Learn More >Gerontological research reveals considerable interindividual variability in aging phenotypes, and emerging evidence suggests that high impact chronic pain may be associated with various accelerated biological aging processes. In particular, epigenetic aging is a robust predictor of health-span and disability compared to chronological age alone. The current study aimed to determine whether several epigenetic aging biomarkers were associated with high impact chronic pain in middle to older age adults (44-78 years old). Participants ( = 213) underwent a blood draw, demographic, psychosocial, pain and functional assessments. We estimated five epigenetic clocks and calculated the difference between epigenetic age and chronological age, which has been previously reported to predict overall mortality risk, as well as included additional derived variables of epigenetic age previously associated with pain. There were significant differences across Pain Impact groups in three out of the five epigenetic clocks examined (DNAmAge, DNAmPhenoAge and DNAmGrimAge), indicating that pain-related disability during the past 6 months was associated with markers of epigenetic aging. Only DNAmPhenoAge and DNAmGrimAge were associated with higher knee pain intensity during the past 48 h. Finally, pain catastrophizing, depressive symptomatology and more neuropathic pain symptoms were significantly associated with an older epigenome in only one of the five epigenetic clocks (i.e. DNAmGrimAge) after correcting for multiple comparisons (corrected 's < 0.05). Given the scant literature in relation to epigenetic aging and the complex experience of pain, additional research is needed to understand whether epigenetic aging may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.
Learn More >Chronic pain is highly prevalent in treatment-seeking opioid-dependent patients; therefore, this comorbid presentation is an important clinical consideration for both addiction and pain specialists. The objectives of the present study were to examine whether the direction of causal attribution of opioid dependence disorder and chronic pain resulted in two distinct clinical populations, and, if so, to compare treatment received during the 5-year follow-up period.
Learn More >Forkhead box O1 (FoxO1) is a critical molecule in modulating cell growth, differentiation and metabolism, acting as a vital transcription factor. This study explored the role of FoxO1 in chronic constriction injury (CCI)-induced neuropathic pain (NP). Microglial and astrocyte activation was achieved with lipopolysaccharide (LPS, 100 ng/mL) to establish an NP model. Morphological alterations in LPS-induced microglia and astrocytes were assayed by light microscopy. The levels of inflammatory cytokines and proteins in microglia and astrocytes were gauged by enzyme-linked immunosorbent assay (ELISA), and Western blot (WB). The CCI-induced NP rat model was constructed for investigating the FoxO1-AQP5 axis in NP. LPS markedly expanded the expression of inflammatory factors and boosted the expression of FoxO1 and AQP5 in microglia and astrocytes. Inhibition of FoxO1 or AQP5 dramatically decreased the LPS-induced inflammation in microglia and astrocytes. , CCI exacerbated the inflammatory response and NP symptoms and substantially raised the contents of FoxO1 and AQP5 in rats' spinal cord tissues. Intrathecal administration of the Sirt1 agonist Resveratrol abated CCI-induced activation of FoxO1 and AQP5, abrogated CCI-induced mechanical hyperalgesia and thermal hyperalgesia, depressed microglial and astrocyte activation, and declined the generation of pro-inflammatory mediators in spinal cord tissues. Mechanistically, blocking the FoxO1-AQP5 pathway inactivated the ERK and p38 MAPK pathways. Suppressing the FoxO1-AQP5 axis alleviated CCI-induced NP and inflammatory responses by modulating the ERK and p38 MAPK signaling pathways.
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