Pain
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The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by posttranslational modifications, creating a code that controls protein function in time and space. Phosphorylation is an important posttranslational modification that affects ∼30% of proteins in vivo. ⋯ This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5 substrates that have been linked to nociceptive pathways, including channels (eg, transient receptor potential cation channel and voltage-gated calcium channel), proteins involved in neurotransmitter release (eg, synaptophysin and collapsin response mediator protein 2), and receptors (eg, glutamate, purinergic, and opioid). By altering the phosphoregulatory "set point" of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.
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Chronic widespread pain conditions are more prevalent in women than men, suggesting a role for gonadal hormones in the observed differences. Previously, we showed that female mice, compared to male, develop widespread, more severe, and longer-duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype. ⋯ We examined potential sex differences in the distribution of SERT across brain sites involved in nociceptive processing using immunohistochemistry. A sex difference in SERT was found in the NRM in the activity-induced pain model; females had greater SERT immunoreactivity than males. This suggests that testosterone protects against development of widespread, long-lasting muscle pain and that alterations in SERT may underlie the sex differences.
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Observational Study
Pain trajectory defines knee osteoarthritis subgroups: a prospective observational study.
Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). ⋯ Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.
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Low back pain (LBP) is a leading cause of work disability. While absent from work, workers with LBP may receive income support from a system such as workers' compensation or social security. This study examines how and in what contexts income support systems impact the healthcare quality for people with work disability and LBP and their functional capacity. ⋯ They also influence worker functional capacity through the level of participation and financial incentives for employers, measures to prove the validity of the worker's LBP, and certain administrative procedures. These mechanisms are often exclusively context-dependent, and generate differing and unintended outcomes depending on features of the healthcare and income support system, as well as other contextual factors such as socioeconomic status and labour force composition. Research and policy design should consider how income support systems may indirectly influence workers with LBP through the workplace.