Analgesic and antiinflammatory effects of two novel kappa-opioid peptides

Background: This study investigates two new K-agonist tetrapeptides, FE 200 665 and FE 200666, with high peripheral selectivity as a result of poor cen tral nervous system penetration, Methods: Four days after administration of Freund adjuvant into the hind pa w of male Wistar rats, antinociceptive effects of intraplantar and subcutan eous injection of FE 200665 and FE 200666 were measured by paw pressure alg esiometry and compared with the K-agonist U-69,593. Peripheral and K-recept or selectivity was assessed by the antagonists naloxone methiodide (NLXM) a nd nor-binaltorphimine, respectively. Antiinflammatory effects were evaluat ed by paw volume plethysmometry and histologic score. Results: Similar to intraplantar U-69,593, intraplantar FE 200665 (3-100 mu g) and FE 200666 (1-30 mug) resulted in significant and dose-related increa ses of paw pressure thresholds. Higher doses of FE 200665 (0.2-20 mg) and F E 200666 (0.06-6 mg) were required by subcutaneous route to produce similar antinociceptive responses, supporting a peripheral site of action. nor-Bin altorphimine dose-dependently antagonized this effect, implying K-opioid se lectivity. Analgesic effects of subcutaneous FE 200665 and FE 200666 were a bolished by intraplantar nor-binaltorphimine, and both subcutaneous and int raplantar effects were dose-dependently antagonized by subcutaneous NLXM, f urther demonstrating a peripheral site of action. One to 6 days after Freun d adjuvant inoculation, single and repeated intraplantar injections of FE 2 00665, FE 200666, and U-69,593 significantly reduced paw volume and histolo gic scores. Both changes were reversed by intraplantar nor-binaltorphimine and subcutaneous NLXM. Conclusion: FE 200665 is a peripherally selective K-agonist with potent ana lgesic and antiinflammatory properties that may lead to improved analgesic- antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.