Pain
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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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Patient-reported outcome measures are being developed for more relevant assessments of pain management. The patient acceptable symptom state (PASS) ("feeling well") and the minimal clinically important improvement (MCII) ("feeling better") have been determined in clinical trials, but not in daily pain management. We carried out a national multicenter cohort study of patients over the age of 50years with painful knee osteoarthritis (KOA) or hip osteoarthritis (HOA) who had visited their general practitioner and required treatment for more than 7days. ⋯ This improvement is smaller than that recorded in randomized controlled trials, and was the same for both sites, both at rest and on movement. In conclusion, patient-reported outcome values in daily practice differ from those in clinical trials, and their determinant factors may depend on the site of osteoarthritis. Assessments of the treatment of painful osteoarthritis should be adapted to the characteristics and daily life of the patient, to personalize patient management.
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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.