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

Tyr‐ D ‐Ala‐Phe‐Leu‐Arg ψ (CH 2 NH) Arg‐NH 2 (SK‐9709) is a dynorphin derivative in which the peptide bond was replaced with a ψ (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) μmol 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 μmol kg −1 , s.c.). The effects of SK‐9709 (s.c.) were also reversed by the selective μ‐opioid receptor antagonist β‐funaltrexamine (4.7 nmol per mouse, i.c.v.), and κ‐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) μmol 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 μ‐ and spinal κ‐opioid receptors.British Journal of Pharmacology (2001) 132 , 1948–1956; doi: 10.1038/sj.bjp.0703982