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Platinum-based chemotherapeutics still play an important role in cancer therapy, however, severe side effects, such as painful neuropathy, occur frequently. The pathophysiologic mechanisms depend on the applied chemotherapeutic agent and are still controversial. In addition to neuronal damage, disturbance of glial cell activity may contribute to neurotoxicity. Here, we focused on the effect of oxaliplatin on satellite glial cell (SGC) function and on the activity of the dorsal root ganglion (DRG) neurons. SGCs were isolated as high-purity cultures and treated with 1 and 10 μM oxaliplatin for 2, 4 and 24 h. Subsequently, glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), Connexin-43 (Cx-43), and inward rectifier potassium channel 4.1 (K) expression was determined by immunocytochemical staining (ICC) and Western blot analyses. Immunochemical staining and Western blot analysis showed an increase in the immune reactivity (IR) and protein levels of ROS, GFAP, and Cx-43. Furthermore, reduction of the IR and protein levels and current density were demonstrated using patch-clamp measurements, of K channels after oxaliplatin exposure. Cytokine release in SGCs was measured using enzyme-linked immunosorbent assays (ELISA) after oxaliplatin exposure and indicated an increased release of IL-6 and TNFα, while IL-1β was decreased. The direct influence of SGC-secreted factors in the supernatant after oxaliplatin treatment led to the hyperexcitability of cultured DRG neurons. In summary, oxaliplatin has a direct impact on the modulation and function of different SGC proteins. Furthermore, SGC-released factors influence the excitability of sensory neurons, qualifying SGCs as potential targets for the prevention and treatment of oxaliplatin-induced polyneuropathy.
Learn More >Despite similar distribution patterns and intracellular events observed in the nociceptin/orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and non-peptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptorrelated ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
Learn More >Pain is considered a hardwired signal of bodily disturbance belonging to a basic motivational system that urges the individual to act and to restore the body's integrity, rather than just a sensory and emotional experience. Given its eminent survival value, pain is a strong motivator for learning. Response to repeated pain increases when harm risks are high (sensitization) and decreases in the absence of such risks (habituation). Discovering relations between pain and other events provides the possibility to predict (Pavlovian conditioning) and control (operant conditioning) harmful events. Avoidance is adaptive in the short term but paradoxically may have detrimental long-term effects. Pain and pain-related responses compete with other demands in the environment. Exposure-based treatments share the aim of facilitating or restoring the pursuit of individual valued life goals in the face of persistent pain, and further improvements in pain treatment may require a paradigm shift toward more personalized approaches. Expected final online publication date for the , Volume 16 is May 7, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >Attending towards pain is proposed as a key mechanism influencing the experience and chronification of pain. Persistent attention toward pain is proposed to drive poor outcomes in both adults and children with chronic pain. However, there are no validated self-report measures of pain-related attention for children.
Learn More >Recent evidence from event-related potentials (ERPs) has identified N2 posterior contralateral (pc) amplitudes as a neural marker of early attention allocation. The N2pc has been used to evaluate attention biases (ABs) in samples with anxiety-based problems but its utility has yet to be considered among persons with chronic pain, another group theorized to display ABs that perpetuate their difficulties. To address this gap, we assessed N2pc responses of adults with chronic pain (N = 70) and pain-free controls (N = 70) during a dot-probe task comprising painful-neutral and happy-neutral facial expression image pairs. Analyses indicated that (1) larger N2pc amplitudes were elicited by both painful and happy expressions compared to complementary neutral expressions in each sample, (2) the chronic pain sample displayed larger N2pc amplitudes during exposure to both painful and happy expressions than controls did, and (3) no group differences were evident for N2pc latencies. Overall N2pc results reflected general biases in early allocation of attention toward affectively-valenced expressions rather than pain-specific ABs among chronic pain cohorts.
Learn More >Many questions regarding the process by which self-enhancing humor style has an effect on chronic pain individuals' adjustment remain unanswered. The aim of the present study was to analyse the association of self-enhancing humor style with adjustment in a sample of individuals with chronic pain, over and above the role of catastrophizing and pain intensity. Adjustment was assessed using measures of depression, pain interference, and flourishing. We also examined the indirect association between self-enhancing humor style and adjustment via pain acceptance.
Learn More >Cumulative evidence supports the association between perceived childhood neglect and adulthood psychological and physical health. To date, pathways mediating this association remain largely unknown, though other evidence suggests that negative patterns of appraisal, including injustice perception related to pain, may be shaped by prior adverse social experiences. Consequently, the current study examined perceived injustice about chronic pain as a possible factor connecting childhood neglect and pain-related outcomes, given its relevance for both adaptation to chronic pain and to prior adverse life experiences. Patients (n = 742) visiting a tertiary pain clinic completed a survey administered via the Collaborative Health Outcomes Information Registry. Path modeling analyses were used to examine perceived injustice as a mediator of the relationships between childhood neglect and affective distress and physical function, after controlling for pain intensity and pain catastrophizing. Patients endorsing childhood neglect reported higher levels of perceived injustice and worse affective distress and physical function. Further, inclusion of perceived injustice as a mediator fully accounted for the relationship between neglect and current levels of physical function, and accounted for a significant proportion of the relationship between neglect and current levels of affective distress. These preliminary findings suggest that perceived injustice appears to be a more proximal factor by which prior experiences of neglect may adversely affect adaptation to chronic pain. Given the single-item assessment of childhood neglect and cross-sectional nature of the current findings, further research may focus on replicating these findings in longitudinal studies with validated measures and examining other adverse social experiences (e.g., abuse, social disparities) that may contribute to injustice perception and poor pain-related outcomes.
Learn More >Cluster headache is a rare form of headache associated with sleep and even speculated to be a manifestation of a sleep disorder rather than a primary headache. Cluster headache exhibits both circadian and circannual rhythmicity. While attacks often occur during sleep, the implication that cluster headaches might be involved with rapid eye movement (REM) sleep phases has neither been fully established nor refuted. The regulatory mechanisms governing sleep including hypothalamic activity and the autonomic nervous system response may play a role. Hypothalamic activation has been observed in cluster headache patients during positron emission tomography testing, but only during attacks. While sleep apnea is associated with morning headaches in general, the link between sleep-disordered respiration and cluster headache remains elusive. Hypoarousal during sleep and periods of hypoxia are associated with cluster headache, the latter likely involving inflammatory processes rather than apnea. Further study is needed, as cluster headaches represent a serious primary cephalgia that is incompletely understood.
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