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The plasma of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene-Related Peptide (iCGRP) release as a measure of nociceptor activation and found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the mM range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We showed that also at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the μM range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an over-additive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of TRPV1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.
Learn More >Virtual reality (VR) technologies have been shown to be beneficial in various areas of healthcare; to date, there are no systematic reviews examining the effectiveness of VR technology for the treatment of spinal pain.
Learn More >Objective Robust evidence suggests children's catastrophizing about their own pain is a risk factor for poor child pain-related outcomes. In children of parents with chronic pain, child catastrophizing about their parents' pain might be a unique predictor of child pain-related outcomes given their increased exposure to parental chronic pain and disability. The objective of this study was to examine associations between child and parent catastrophizing about their own and each other's pain and child and parent pain-related outcomes. Methods Seventy-two parents with chronic pain and their children (ages 8-15) completed questionnaires assessing their trait catastrophizing about their own and each other's pain, their own pain, and the child's internalizing symptoms. Children completed the cold pressor task (CPT) in the presence of their parent. Parents and children rated children's worst pain intensity and their own anxiety during the task. Analyses were guided by the Actor-Partner Interdependence Model. Results Greater child catastrophizing about parent pain was associated with children's and parents' increased catastrophizing about their own pain. Child catastrophizing about parent pain was associated with greater child- and parent-reported child internalizing symptoms and greater CPT pain intensity for the child, but not parent/child usual pain or CPT anxiety, over and above the influence of parent and child catastrophizing about their own pain. Conclusions Child catastrophizing about parent pain is a potential vulnerability factor associated with poor pain-related outcomes in children of parents with chronic pain that should be considered in future research and clinical settings. Statement of contribution What is already known on this subject? Higher rates of pain and internalizing symptoms are observed in offspring of parents with vs. without chronic pain. Greater child and parent pain catastrophizing are associated with poorer pain-related outcomes in children. Child catastrophizing about parent chronic pain and its association with child outcomes has not been examined. What does this study add? Greater child catastrophizing about parent chronic pain is associated with greater child internalizing and CPT pain. These effects were seen beyond the association of child and parent catastrophizing about their own pain.
Learn More >Glycine neurotransmission in the dorsal horn of the spinal cord plays a key role in regulating nociceptive signaling, but in chronic pain states reduced glycine neurotransmission is associated with the development of allodynia and hypersensitivity to painful stimuli. This suggests that restoration of glycine neurotransmission may be therapeutic for the treatment of chronic pain. Glycine Transporter 2 inhibitors have been demonstrated to enhance glycine neurotransmission and provide relief from allodynia in rodent models of chronic pain. In recent years, photoswitchable compounds have been developed to provide the possibility of controlling the activity of target proteins using light. In this study we have developed a photoswitchable non-competitive inhibitor of Glycine Transporter 2 that has different affinities for the transporter at 365 nm compared to 470 nm light.
Learn More >Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7; however, the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-S2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.
Learn More >Chronic radicular neuropathic pain is a major clinical problem with a life time prevalence of more than 50%. Pulsed radiofrequency (PRF) treatment is a recognised therapy. However, the pathophysiology of chronic neuropathic pain (CNP) and the mechanism of action of PRF remains ill-defined. Improving our knowledge of the mechanisms of CNP and PRF action will enhance our ability to treat patients with this common debilitating problem more effectively. This study aims to characterise the CSF cellular and peptide constituents in patients with CNP and the effect of pulsed radiofrequency (PRF) on these constituents and reported pain.
Learn More >Registry based repeated-measures psychometric validation of the Danish Oswestry Disability Index (ODI) OBJECTIVE.: The goal was to use classical and modern psychometric validation methods to assess the measurement properties and the minimally clinical important difference (MCID) of the ODI in a Danish cohort of patients with chronic low back pain (LBP) being treated with spinal surgery.
Learn More >Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg· d, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg· d, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.
Learn More >The growing presence of artificial lighting across the globe presents a number of challenges to human and ecological health despite its societal benefits. Exposure to artificial light at night, a seemingly innocuous aspect of modern life, disrupts behavior and physiological functions. Specifically, light at night induces neuroinflammation, which is implicated in neuropathic and nociceptive pain states, including hyperalgesia and allodynia. Because of its influence on neuroinflammation, we investigated the effects of dim light at night exposure on pain responsiveness in male mice. In this study, mice exposed to four days of dim (5 lux) light at night exhibited cold hyperalgesia. Further, after 28 days of exposure, mice exhibited both cold hyperalgesia and mechanical allodynia. No heat/hot hyperalgesia was observed in this experiment. Altered nociception in mice exposed to dim light at night was concurrent with upregulated interleukin-6 and nerve growth factor mRNA expression in the medulla and elevated μ-opioid receptor mRNA expression in the periaqueductal gray region of the brain. The current results support the relationship between disrupted circadian rhythms and altered pain sensitivity. In summary, we observed that dim light at night induces cold hyperalgesia and mechanical allodynia, potentially through elevated central neuroinflammation and dysregulation of the endogenous opioid system.
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