Antinociceptive activity of peptides related to interleukin-1 beta-(193-195), Lys-Pro-Thr

A series of closely related peptide analogues of Lys-Pro-Thr [(interleukin-1 beta-(193-195)] have been investigated in two models of antinociception in mice (acetic acid-induced abdominal constrictions and formalin tests) and compared with morphine, aspirin and indomethacin. Formalin-induced nociceptive responses in the mouse showed early (0-5 min) and late (15-30 min) phases of peak activity. Lys-D-Pro, Lys-D-Pro-Thr, Lys-D-Pro-Arg, Lys-D-Pro-Val, morphine and aspirin, were antinociceptive in both phases after intraperitoneal (i.p.) and oral (p.o.) administrations. Lys-D-Pro-Leu inhibited the early phase response only after i.p. injection. Lys-D-Pro-Val-NH2, Lys-D-Pro-Gln, Lys-D-Pro-Tyr, Lys-D-Pro-Asn, Asp-Lys-D-Pro-Val and indomethacin were active only against the late phase (ED50 values of 64, 32, 44, 94, 67 and 25 mg/kg i.p., respectively). Several of the peptides showed good bio-availability, e.g. Lys-D-Pro-Asn (ED50: 10 mg/kg i.p.; 11.4 mg/kg p.o.) in the abdominal constrictions test, where two modes of action were apparent, non-opioid and opioid; non-opioid (naloxone-insensitive antinociception) mechanisms were illustrated by Lys-D-Pro-Thr and Lys-D-Pro-Asn; opioid (naloxone-sensitive antinociception) mechanisms by Lys-D-Pro-Val and Lys-D-Pro-Leu. These data identify orally active antinociceptive peptides in both antinociceptive tests with varied relative potency profiles to morphine, indomethacin and aspirin in the mouse formalin test.