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Acceptance and commitment therapy (ACT) can be effective in treating chronic pain. Despite evidence supporting the effectiveness of ACT, uncertainties remain regarding which subgroups in the chronic pain population are likely to benefit most and least. This protocol describes the application for two meta-analytic approaches, one at the level of individual participant data and the other at the level of aggregated data, from randomized controlled trials of ACT for chronic pain (ACT-CP-MA).
Learn More >In recent years, mammalian Glycine transporter 2 (GlyT2) has emerged as a promising target for the development of compounds against chronic pain states. In our current work, we discovered a new set of promising hits that inhibit the glycine transporter at nano- and micromolar activity and have excellent selectivity over GlyT1 (as shown by studies) using a newly designed virtual screening (VS) protocol that combines a structure-based pharmacophore and docking screens with a success rate of 75%. Furthermore, the free energy perturbation calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Hit1 compound. The FEP+ results well-matched with the available literature mutational data proving the quality of the generated GlyT2 structure. On the basis of these results, we propose that our hit compounds may lead to new chronic pain agents to address unmet and challenging clinical needs.
Learn More >The epidermal barrier is thought to protect sensory nerves from overexposure to environmental stimuli, and barrier impairment leads to pathological conditions associated with itch, such as atopic dermatitis (AD). However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. Here we show that epidermal nerves are contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of chronic itch caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we found that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs in the normal skin, whereas this process was disturbed during chronic itch development. Furthermore, aberrant Ca increases in epidermal nerves were induced in association with the disturbed pruning. Finally, TRPA1 inhibition suppressed aberrant Ca increases in epidermal nerves and itch. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to aberrant activation of epidermal nerves and pathological itch.
Learn More >Questionnaire-based headache diagnoses should be validated against diagnoses made by the gold standard, which is personal interview by a headache expert. The diagnostic algorithm with the best diagnostic accuracy should be used when later analysing the data.
Learn More >Many trigeminal neuropathic pain patients suffer severe chronic pain. The neuropathic pain might be related with cross-excitation of the neighboring neurons and satellite glia cells (SGCs) in the sensory ganglia and increasing the pain signals from the peripheral tissue to the central nervous system. We induced trigeminal neuropathic pain by infraorbital nerve constriction injury (IONC) in Sprague-Dawley rats. We tested cytokine (CXCL2 and IL-10) levels in trigeminal ganglia (TGs) after trigeminal neuropathic pain induction, and the effect of direct injection of the anti-CXCL2 and recombinant IL-10 into TG. We found that IONC induced pain behavior. Additionally, IONC induced satellite glial cell activation in TG and cytokine levels of TGs were changed after IONC. CXCL2 levels increased at day 1 of neuropathic pain induction and decreased gradually, with IL-10 levels showing the opposite trend. Recombinant IL-10 or anti-CXCL2 injection into TG decreased pain behavior. Our results show that IL-10 or anti-CXCL2 are therapy options for neuropathic pain.
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