[D-Pro10]-dynorphin(1-11) is a kappa-selective opioid analgesic in mice

Abstract

The synthetic opioid agonist [D-Pro10]-dynorphin(1-11) (DPDYN) binds kappa receptors with both high affinity and selectivity in vitro. We have examined the in vivo characteristics (i.e., analgesic properties) of the peptide in mice. The analgesic effects of i.c.v. administered DPDYN were determined in two nociceptive tests, involving thermal cutaneous (tail-flick) and chemical visceral (AcOH-induced writhing) stimuli, in which mu and kappa receptors are known to be activated differentially. The antinociceptive action of DPDYN was compared with that of 1) morphine and U-50,488H, which are, respectively, the prototypical mu and kappa agonists, 2) dynorphin A which is the endogenous parent peptide and 3) Leu-enkephalin, which represents the N-terminal sequence of DPDYN. DPDYN did not show any activity against thermal stimulus but, in contrast, produced a dose-related effect against chemical pain. In the AcOH-writhing test, there was no significant cross-tolerance between morphine and DPDYN in mice made tolerant to morphine. Pretreatment with low doses of s.c. naloxone (less than 1 mg/kg) antagonized completely the antinociceptive action of morphine but only partially reversed the analgesic action of DPDYN. In gastrointestinal studies, DPDYN as well as U-50,488H were ineffective (maximum effect lower than 25%) in inhibiting intestinal transit in mice, in contrast to morphine which produced a dose-related antitransit effect reaching 100%. These data indicate that the in vivo properties, and particularly analgesia, of i.c.v. administered DPDYN are mediated by a "non-mu" (presumably kappa) opioid receptor at the supraspinal level of the opioid system of the mouse.