Long-lasting antinociceptive effects of a novel dynorphin analogue, Tyr-D-Ala-Phe-Leu-Arg psi (CH2NH) Arg-NH2, in mice

1 Tyr-D-Ala-Phe-Leu-Arg psi (CH2NH) Arg-NH2 (SK-9709) is a dynorphin deriva tive in which the peptide bond was replaced with a psi (CH2NH) bond. In the present study, the antinociceptive effects of SK-9709 were determined in a n acetic acid-induced writhing test and a hot-plate test. 2 In the acetic acid-induced writhing test, significant antinociceptive eff ects were observed after subcutaneous (s.c.), intracerebroventricular (i.c. v.) and intrathecal (i.t.) injection of SK-9709, with maximal effects at 12 0, 30 and 15 min, respectively. The antinociceptive effects were dose-depen dent and ED50 values (range of 95% confidence limits) after s.c., i.c.v, an d i.t. injection were 1.36 (0.61-3.02) mu mol kg(-1), 2.11 (1.18-3.79) and 0.79 (0.61-1.03) nmol per mouse, respectively. 3 The effects of SK-9709 (s.c., i.c.v. and i.t.) were reversed by the opioi d receptor antagonist naloxone (1.36 mu mol kg(-1), s.c.). The effects of S K-9709 (s.c.) were also reversed by the selective mu -opioid receptor antag onist beta -funaltrexamine (4.7 nmol per mouse, i.c.v.), and kappa -opioid receptor antagonist nor-binaltorphimine (4.9 nmol per mouse, i.t.). 4 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 antinoc iceptive effects were dose-dependent and ED50 values (range of 95% confiden ce limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4-283.0) mu m ol kg(-1), 6.5 (4.0-10.7) and 7.4 (5.0-11.0) nmol per mouse, respectively. 5 These findings indicated that systemically administered SK-9709 produced long-lasting antinociceptive effects and these effects were mediated by bot h supra-spinal mu- and spinal kappa -opioid receptors.