Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1-8) in rats

Previous in vitro studies showed that the degradation of dynorphin-(1-8) [d yn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) admini stration of dyn(1-8) were examined. The inhibitory effect of dyn-(1-8) on t he tail-flick response was increased more than 100-fold by the i.t.v. pre t reatment of rats with the three PIs. The inhibition produced by dyn-(1-8) in rats pretreated with any combinatio n of two PIs was significantly smaller than that in rats pretreated with th ree PIs, indicating that any residual single peptidase could inactivate sig nificant amounts of dyn(1-8). The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is med iated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met(5 )]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtaine d in previous studies strongly indicate that dyn-(1-8) not only has well-kn own kappa-agonist activity but also has high mu-agonist activity.