Articles: hyperalgesia-pathology.
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Persistent pain after resolution of clinically appreciable signs of arthritis poses a therapeutic challenge, and immunosuppressive therapies do not meet this medical need. To investigate this conversion to persistent pain, we utilized the K/BxN serum transfer arthritis model, which has persistent mechanical hypersensitivity despite the resolution of visible inflammation. Toll-like receptor (TLR) 4 has been implicated as a potential therapeutic target in neuropathic and other pain models. ⋯ WT arthritic mice had reduced spinal levels of the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) on day 6, compared to IT LPS-RS-treated mice. Direct IT application of 15d-PGJ(2) (0.5 μg) on day 6 improved mechanical hypersensitivity in arthritic mice within 15 min. Hence, TLR4 signaling altered spinal bioactive lipid profiles in the serum transfer model and played a critical role in the transition from acute to chronic postinflammatory mechanical hypersensitivity.
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Comparative Study
Genotype-selective phenotypic switch in primary afferent neurons contributes to neuropathic pain.
Pain is normally mediated by nociceptive Aδ and C fibers, while Aβ fibers signal touch. However, after nerve injury, Aβ fibers may signal pain. Using a genetic model, we tested the hypothesis that phenotypic switching in neurotransmitters expressed by Aβ afferents might account for heritable differences in neuropathic pain behavior. ⋯ Substance P immunoreactivity was also upregulated in large-diameter neurons, but this change was similar in the 2 lines. Our findings suggest that phenotypic switching contributes to the heritable difference in pain behavior in HA vs LA rats. Specifically, we propose that in HA rats, but less so in LA rats, injured, spontaneously active Aβ afferents both directly drive CGRP-sensitive central nervous system pain-signaling neurons and also trigger and maintain central sensitization, hence generating spontaneous pain and tactile allodynia.
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Mitochondria are present at high concentration at the site of sensory transduction in the peripheral terminals of nociceptors. Because nerve growth factor (NGF), which induces nociceptor sensitization by acting on the high-affinity tropomyosin receptor kinase A (TrkA) receptor, also produces local recruitment of mitochondria in DRG neurons, we evaluated the role of mitochondria in NGF-induced mechanical hyperalgesia. ⋯ Disruption of microtubules, which are required for the trafficking and subcellular localization of mitochondria, also attenuated NGF-induced hyperalgesia. Our results suggest a contribution of mitochondrial localization and function to NGF-dependent pain syndromes.
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GABA and glutamate are both affected by stress and are involved in nociception. Thus, we determined whether stress-induced enhancement of inflammatory hyperalgesia is mediated by an imbalance between glutamate and GABA neurotransmission. Male rats were subjected daily to 10 to 20 minutes per day of either forced swimming (FS) or sham swimming for 3 consecutive days; nonconditioned rats served as controls. ⋯ Diazepam effects were blocked by flumazenil. NO(x) increased in lumbar spinal cord of FS rats by a mechanism antagonized by ketamine. Thus, stress-induced hyperalgesia is initiated by a decreased and delayed GABA release and GABA-A receptor activation, whereas it is maintained by increased glutamate release and NMDA glutamate receptor activation at the spinal level.
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Evidence suggests large diameter afferents, presumably in response to centrally mediated changes, augment the mechanical allodynia or hyperalgesia seen in delayed onset muscle soreness (DOMS) conditions. Healthy males aged 18 to 30 (n = 16) performed eccentric exercise eliciting DOMS in the tibialis anterior muscle of a randomly assigned exercised leg. The contralateral leg served as a control. Mechanosensitivity was assessed on the exercised and control legs prior to and 24 hours postexercise via pressure pain thresholds (PPTs). PPTs were assessed at the muscle site, and at a distant segmentally related site, either without vibration or with vibration concurrently applied to the distant muscle, segmentally related, or control extra-segmentally related site. Participants completed a 6-point Likert scale providing a subjective measure of DOMS 5 days postexercise. Baseline mechanosensitivity was not significantly different at any site between the exercised and control legs prior to the exercise. Soreness ratings were higher 24 to 48 hours postexercise (P < .05), and baseline PPTs at the exercised legs muscle site decreased postexercise (P < .001). On day 1 following exercise, segmentally related site PPTs reduced significantly when vibration was applied concurrently to the DOMS affected tibialis anterior muscle (P < .04) compared to baseline mechanosensitivity or extrasegmental control vibration. ⋯ Further evidence is presented by this article indicating that large diameter afferents, presumably via centrally mediated mechanisms, augment the mechanical hyperalgesia seen in DOMS conditions. Future research examining eccentric activity in individuals with likely centrally sensitized conditions may be warranted.