Pain
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N-methyl-D-aspartate receptor (NMDAR) antagonists have been shown to reduce mechanical hypersensitivity in animal models of inflammatory pain. However, their clinical use is associated with significant dose-limiting side effects. Small-conductance Ca-activated K channels (SK) have been shown to modulate NMDAR activity in the brain. ⋯ Double immunostaining shows coexpression of SK3 and NMDAR subunit, NR1, compatible with functional interaction. Moreover, we demonstrate that i.t. coadministration of NS309 with an NMDAR antagonist reduces the dose of NMDAR antagonist, DL-2-amino-5-phosphonopentanoic acid (DL-AP5), required to produce antinociceptive effects in the CFA model. This reduction could attenuate the unwanted side effects associated with NMDAR antagonists, giving this combination potential clinical implications.
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Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is sufficient to induce a chronic pain state through extracellular signal-regulated kinase (ERK) signaling to protein synthesis machinery. We have further tested whether the maintenance of this chronic pain state involves a brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (trkB)/atypical protein kinase C (aPKC) signaling axis. ⋯ Systemic injection of the trkB antagonist ANA-12 similarly inhibited PAR2-mediated mechanical hypersensitivity, grimacing, and hyperalgesic priming. Inhibition of aPKC (intrathecal delivery of ZIP) or trkB (systemic administration of ANA-12) after the resolution of 2-at-induced mechanical hypersensitivity reversed the maintenance of hyperalgesic priming. Hence, PAR2 activation is sufficient to induce neuronal plasticity leading to a chronic pain state, the maintenance of which is dependent on a BDNF/trkB/aPKC signaling axis.
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Randomized Controlled Trial
Automated, Internet-based Pain Coping Skills Training to Manage Osteoarthritis Pain: A Randomized Controlled Trial.
Osteoarthritis (OA) places a significant burden on worldwide public health because of the large and growing number of people affected by OA and its associated pain and disability. Pain coping skills training (PCST) is an evidence-based intervention targeting OA pain and disability. To reduce barriers that currently limit access to PCST, we developed an 8-week, automated, Internet-based PCST program called PainCOACH and evaluated its potential efficacy and acceptability in a small-scale, 2-arm randomized controlled feasibility trial. ⋯ Additionally, both men and women demonstrated increases in self-efficacy from baseline to after intervention compared with the control group (d = 0.43). Smaller effects were observed for pain-related anxiety (d = 0.20), pain-related interference with functioning (d = 0.13), negative affect (d = 0.10), and positive affect (d = 0.24). Findings underscore the value of continuing to develop an automated Internet-based approach to disseminate this empirically supported intervention.