Comparative spinal analgesic action of dynorphin1-8, dynorphin1-13, and a kappa-receptor agonist U50,488

The effect of intrathecal injections of dynorphin1-8 (DYN1-8), dynorphin1-13 (DYN1-13), and a putative kappa agonist, U50,488 was tested in the rat tail-flick test. DYN1-8 and DYN1-13 (5, 10, 20 micrograms) produced a dose-related biphasic antinociceptive response consisting of an initial and a delayed response. Injection of U50,488 (20, 40 60 micrograms) produced a monophasic response. The antinociceptive effect of DYN1-8 (5, 10, 20 micrograms) and DYN1-13 (20 micrograms), was present 24 h postintrathecal injection. Pretreatment with systemic naloxone (2 mg/kg s.c.) attenuated the delayed response, but not the initial response induced by DYN1-8 and DYN1-13. The initial response was attenuated by pretreatment with intrathecal naloxone at a dose of 0.5 and 2.0 micrograms. The antinociceptive effect of U50,488 (20, 60 micrograms) was not affected by pretreatment with 2.0 micrograms intrathecal naloxone, but was significantly reduced by 4 micrograms of the antagonist. Both DYN1-8 and DYN1-13 (5 micrograms) augmented the antinociceptive effect of intrathecally administered morphine (5, 10 micrograms). Intrathecal injection of DYN1-8 (5, 10, 20 micrograms), DYN1-13 (5 micrograms), and morphine (10 micrograms) reduced the spontaneous output of urine measured at 2 and 24 h postintrathecal injection. A similar injection of U50,488 (20 micrograms) had no significant action on the urinary output. The results show that long and short dynorphin fragments have a comparable activity and the spinal antinociceptive actions of dynorphin are sensitive to low doses of intrathecal naloxone. The activity profile of spinally administered dynorphins differs from that of the kappa agonist U50,488.