Long-lasting antinociceptive effects of a novel dynorphin analogue, Tyr-D-Ala-Phe-Leu-Arg psi (CH(2)NH) Arg-NH(2), in mice.

Tyr-D-Ala-Phe-Leu-Arg psi (CH(2)NH) Arg-NH(2) (SK-9709) is a dynorphin derivative in which the peptide bond was replaced with a psi (CH(2)NH) bond. In the present study, the antinociceptive effects of SK-9709 were determined in an acetic acid-induced writhing test and a hot-plate test. In the acetic acid-induced writhing test, significant antinociceptive effects were observed after subcutaneous (s.c.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) injection of SK-9709, with maximal effects at 120, 30 and 15 min, respectively. The antinociceptive effects were dose-dependent and ED(50) values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 1.36 (0.61 - 3.02) micromol kg(-1), 2.11 (1.18 - 3.79) and 0.79 (0.61 - 1.03) nmol per mouse, respectively. The effects of SK-9709 (s.c., i.c.v. and i.t.) were reversed by the opioid receptor antagonist naloxone (1.36 micromol kg(-1), s.c.). The effects of SK-9709 (s.c.) were also reversed by the selective mu-opioid receptor antagonist beta-funaltrexamine (4.7 nmol per mouse, i.c.v.), and kappa-opioid receptor antagonist nor-binaltorphimine (4.9 nmol per mouse, i.t.). In the hot-plate test, the antinociceptive effect of SK-9709 (s.c., i.c.v. and i.t.) was also dose-dependent with the maximal peak effect at 120, 15 and 15 min similarly to the acetic acid-induced writhing test. The antinociceptive effects were dose-dependent and ED(50) values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4 - 283.0) micromol kg(-1), 6.5 (4.0 - 10.7) and 7.4 (5.0 - 11.0) nmol per mouse, respectively. These findings indicated that systemically administered SK-9709 produced long-lasting antinociceptive effects and these effects were mediated by both supra-spinal mu- and spinal kappa-opioid receptors.