Pain
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Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors, eg, from the Mas-related G-protein-coupled receptor family. ⋯ Lysophosphatidic acid microinjections activated a greater proportion of CMi fibers and more strongly than CM fibers; spicule application of LPA activated CM and CMi fibers to a similar extent but excited CM fibers more and CMi fibers less intensely than microinjections. In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents and a specific combination of activated fiber subclasses might contribute.
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Meta Analysis
Different routes of administration in chronic migraine prevention lead to different placebo responses: a meta-analysis.
Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. ⋯ Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.
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Randomized Controlled Trial
Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.
Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. ⋯ Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.
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Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn are found primarily in laminae II inner and III. Inhibitory PVINs play an important role in segregating innocuous tactile input from pain-processing circuits through presynaptic inhibition of myelinated low-threshold mechanoreceptors and postsynaptic inhibition of distinct spinal circuits. ⋯ Here, we use neuroanatomical and optogenetic approaches to show that ePVINs comprise a larger proportion of the PVIN population than previously reported and that both ePVIN and inhibitory PVIN populations form synaptic connections among (and between) themselves. We find that these cells contribute to neuronal networks that influence activity within several functionally distinct circuits and that aberrant activity of ePVINs under pathological conditions is well placed to contribute to the development of mechanical hypersensitivity.