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HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation.
Learn More >Chronic pelvic pain in women is a complex condition, and physical therapy is recommended as part of a broader treatment approach. The objective of this study was to compare structured group-based multimodal physical therapy in a hospital setting (intervention group) with primary care physical therapy (comparator group) for women with chronic pelvic pain.
Learn More >Recent evidence suggests that insomnia negatively influences the occurrence of generalized pain. This study examined whether insomnia is a risk factor for the transition from local pain to generalized pain (i.e., spreading of pain).
Learn More >When treating migraine patients in the current era of Coronavirus Disease 2019 (COVID-19), many institutions have moved away from face-to-face procedures like onabotulinumtoxinA injections, sometimes transitioning to the newer CGRP antibodies for migraine prevention. However, despite our best efforts to mitigate viral transmission, many of our migraine patients may eventually be exposed to SARS-CoV2. While most patients will have mild to moderate symptoms, a subset will become severely ill, with possible complications including respiratory failure and acute respiratory distress syndrome (ARDS). Given the possibility of this level of severe respiratory illness, we should consider what effect blocking calcitonin gene-related peptide (CGRP) might have on these patients.
Learn More >The mechanisms underlying type-2 diabetic neuropathic pain (DNP) are unclear. This study investigates the coupling of postsynaptic density-95 (PSD-95) to N-methyl-D-aspartate receptor subunit 2B (GluN2B), and the subsequent phosphorylation of GluN2B (Tyr1472-GluN2B) in the spinal cord in a rat model of type-2 DNP. Expression levels of PSD-95, Tyr1472-GluN2B, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its phosphorylated counterpart (Thr286-CaMKII), and α-amino-3-hydroxy-5-methyl-4-soxazole propionic acid receptor subtype 1 (GluR1) and its phosphorylated counterpart (Ser831-GluR1) were significantly increased versus controls in the spinal cord of type-2 DNP rats whereas the expression of total spinal GluN2B did not change. The intrathecal injection of Ro25-6981 (a specific antagonist of GluN2B) or Tat-NR2B9c (a mimetic peptide disrupting the interaction between PSD-95 and GluN2B) induced an antihyperalgesic effect and blocked the increased expression of Tyr1472-GluN2B, CaMKII, GluR1, Thr286-CaMKII, and Ser831-GluR1 in the spinal cords; the increase in spinal cord PSD-95 was not affected. These findings indicate that the PSD-95-GluN2B interaction may increase phosphorylation of GluN2B, and subsequently induce the expression of phosphorylation of CaMKII and GluR1 in the spinal cord of type-2 DNP rats. Targeting the interaction of PSD-95 with GluN2B may provide a new therapeutic strategy for type-2 DNP.
Learn More >Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks.
Learn More >Chronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive and emotional information and in conditioned pain modulation. We previously reported wide-spread epigenetic reprogramming in the PFC many months following nerve injury in rodents. Epigenetic modifications, including DNA methylation, can drive changes in gene expression without modifying DNA sequences. To date, little is known about epigenetic dysregulation at the onset of acute pain or how it progresses as pain transitions from acute to chronic. We hypothesize that acute pain following injury results in rapid and persistent epigenetic remodelling in the PFC that evolves as pain becomes chronic. We further propose that understanding epigenetic remodelling will provide insights into the mechanisms driving pain-related changes in the brain. Epigenome-wide analysis was performed in the mouse PFC 1 day, 2 weeks, 6 months, and 1 year following peripheral injury using the spared nerve injury (SNI) in mice. SNI resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed between SNI and sham-operated control mice at all time points. Hundreds of differentially methylated genes were identified, including many with known function in pain. Pathway analysis revealed enrichment in genes related to stimulus response at early time points, immune function at later time points and actin and cytoskeletal regulation throughout the time course. These results emphasize the importance of considering pain chronicity in both pain research and in treatment optimization.
Learn More >The opioid epidemic has plagued the United States with high levels of abuse and poor quality of life for chronic pain patients requiring continuous use of opioids. New drug discovery efforts have been implemented to mitigate this epidemic, however, new medications are still limited by low efficacy and/or high side effect and abuse potential. Intermittent fasting (IF) has recently been shown to improve a variety of pathological states, including stroke and neuroinflammation. Numerous animal and human studies have shown the benefits of IF in these disease states, but not in pain and opioid treatment. We thus subjected male and female CD-1 mice to 18-hour fasting intervals followed by 6-hour feed periods with standard chow for 1 week. Mice which underwent this diet displayed an enhanced anti-nociceptive response to morphine both in efficacy and duration using thermal tail flick and post-operative paw incision pain models. While showing enhanced anti-nociception, IF mice also demonstrated no morphine reward and reduced tolerance and constipation. Seeking a mechanism for these improvements, we found that the mu opioid receptor (MOR) showed enhanced efficacy and reduced tolerance in the spinal cord and periaqueductal grey (PAG) respectively from IF mice using a S-GTPγS coupling assay. These improvements in receptor function were not due to changes in MOR protein expression. These data suggest that a daily IF diet may improve the therapeutic index of acute and chronic opioid therapies for pain patients in the clinic, providing a novel tool to improve patient therapy and reduce potential abuse.
Learn More >Attentional biases are posited to play a key role in the development and maintenance of chronic pain in adults and youth. However, research to date has yielded mixed findings and few studies have examined attentional biases in pediatric samples. The present study used eye-gaze tracking to examine attentional biases to pain-related stimuli in a clinical sample of youth with chronic pain and pain-free controls. The moderating role of attentional control was also examined. Youth with chronic pain (n = 102) and pain-free controls (n = 53) viewed images of children depicting varying levels of pain expressiveness paired with neutral faces while their eye gaze was recorded. Attentional control was assessed using both a questionnaire and a behavioural task. Both groups were more likely to first fixate on high pain faces but showed no such orienting bias for moderate or low pain faces. Youth with chronic pain fixated longer on all pain faces than neutral faces, whereas youth in the control group exhibited a total fixation bias only for high and moderate pain faces. Attentional control did not moderate attentional biases between or within groups. The results lend support to theoretical models positing the presence of attentional biases in youth with chronic pain. Further research is required to clarify the nature of attentional biases and their relationship to clinical outcomes.
Learn More >Psychological stress is a trigger for the development of irritable bowel syndrome (IBS) and associated symptoms including abdominal pain. Although IBS patients exhibit increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system (CNS) are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are negatively regulated by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator P38 MAPK.
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