Pain
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Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. ⋯ The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P=.006) and SCI-noNP (P=.026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.
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T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist TTA-A2 efficiently inhibits recombinant and native Ca(V)3.2 currents. Although TTA-A2 is a pan Ca(V)3 blocker, it demonstrates a higher potency for Ca(V)3.2 compared to Ca(V)3.1. ⋯ Oral administration of TTA-A2 produced a dose-dependent reduction of hypersensitivity in an IBS model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of TTA-A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with IBS.
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Inflammatory pain severely affects the quality of life of millions of individuals worldwide. Prostaglandin E2 (PGE2), a pain mediator enriched in inflamed tissues, plays a pivotal role in nociceptor sensitization and in the genesis of inflammatory pain. Its EP4 receptor mainly mediates its role in inflammatory pain. ⋯ Intraplantar injection of complete Freud's adjuvant increases both total and cell-surface EP4 levels of L4-6 DRG neurons, an event suppressed by a cyclooxygenase-2 inhibitor or a selective EP4 antagonist, suggesting that PGE2/EP4 signalling in inflamed paw contributes to EP4 synthesis and export in DRG neurons, thus sensitizing nociceptors during inflammation. We conclude that PGE2/EP4 signalling-induced EP4 externalization in DRG neuron is a novel mechanism underlying nociceptor sensitization and inflammatory pain. Blocking EP4 externalization could open a novel therapeutic avenue to treat inflammatory pain.
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Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. ⋯ In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.