Pain
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Neuropathic itch is a pathological condition that is due to damage within the nervous system. This type of itch can be severe and unrelenting, which has a very negative impact on quality of life. ⋯ Unfortunately, much like neuropathic pain, there is a lack of effective treatments for neuropathic itch. Here, we consider the neural basis of itch and then describe how injuries within these neural circuits can lead to neuropathic itch in both animal models and human disease states.
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Nerve growth factor (NGF) injected into the human skin causes local hyperalgesia to mechanical and electrical stimuli lasting for weeks. Pig data suggested axonal sensitization of C-nociceptors as a contributing mechanism. Here, we recorded single C-nociceptors in 11 human subjects 3 weeks after intracutaneous injection of 1 μg NGF into the foot dorsum. ⋯ The sensitization included sensory and axonal components affecting both activation thresholds and supra-threshold responses. Our data suggest that a combination of sensory sensitization and axonal hyperexcitability is underlying the localized hyperalgesia by facilitating action potential generation and conduction. Axonal changes were also found in the asymptomatic skin surrounding the NGF-treatment sites, thereby possibly reflecting "nociceptive priming."
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With less than 50% of patients responding to the current standard of care and poor efficacy and selectivity of current treatments, neuropathic pain continues to be an area of considerable unmet medical need. Biological therapeutics such as monoclonal antibodies (mAbs) provide better intrinsic selectivity; however, delivery to the central nervous system (CNS) remains a challenge. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is well described in inflammation-induced pain, and early-phase clinical trials evaluating its antagonism have exemplified its importance as a peripheral pain target. ⋯ Functional analysis of glial cells revealed that pretreatment with GM-CSF potentiated lipopolysaccharide-induced release of proinflammatory cytokines. In summary, our data indicate that GM-CSF is a proinflammatory cytokine that contributes to nociceptive signalling through driving spinal glial cell secretion of proinflammatory mediators. In addition, we report a successful approach to accessing CNS pain targets, providing promise for central compartment delivery of analgesics.
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Benzodiazepines and opioids are commonly used among veterans suffering from mental health disorders and pain conditions. The objective of this study is to determine whether concomitant benzodiazepine-opioid use increases the incidence of adverse outcomes above the baseline risk of nonacute opioid-only use. The dataset contained all veterans who filled at least 1 opioid prescription during the years 2008 to 2012. ⋯ The final matched sample consisted of 396,141 nonacute opioid-only using veterans and 48,971 concomitant benzodiazepine-opioid users. Receiving opioids and benzodiazepines concomitantly increased the risk of experiencing an adverse outcome with an odds ratio of 1.359 (95% confidence interval: 1.320-1.400; P < 0.0001). Among veterans receiving opioids, concomitant benzodiazepine use is associated with an increased risk of adverse outcomes when compared to the baseline risk of opioid-only using veterans.