Abstract

E-2078 ([N-methyl-Tyr1, N-alpha-methyl-Arg7, D-Leu8]dynorphin A(1-8) ethylamide) is a systemically active dynorphin analog. We examined monoaminergic involvement in the antinociceptive action of E-2078 compared with morphine and U-50,488E (trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)- benzene-acetamide monohydrochloride). The antinociceptive effect of these drugs was determined using the mouse tail-flick test after depletion of norepinephrine or 5-HT by pretreatment with various neurotoxins. Reserpine (i.p.) depleted both norepinephrine and 5-HT. Selective degeneration of noradrenergic nerves was induced by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, i.p.) or intrathecal (i.t.) 6-hydroxydopamine (6-OHDA), whereas 5-HT was depleted by p-chlorophenylalanine (PCPA, i.p.) or 5,7-dihydroxytryptamine (5,7-DHT, i.t.). The antinociceptive action of E-2078 administered s.c. was significantly attenuated in mice treated with reserpine, DSP-4, 6-OHDA, PCPA or 5,7-DHT compared with that in non-neurotoxin animals. Antinociception induced by intracerebroventricular (i.c.v.) and i.t. injection of E-2078 was reversed by reserpine, DSP-4 or PCPA. The antinociceptive action of morphine (s.c.) was attenuated by reserpine, DSP-4, 6-OHDA and PCPA, but not by 5,7-DHT. Antinociception produced by i.c.v. morphine was antagonized by reserpine, DSP-4 and PCPA. In contrast, morphine given i.t. was not affected by these neurotoxins. U-50,488E (s.c.)-induced antinociception was attenuated by reserpine, DSP-4, 6-OHDA, PCPA and 5,7-DHT. Intracerebroventricular U-50,488E was antagonized by reserpine, DSP-4 and PCPA, whereas i.t. U-50,488E was reversed only by reserpine and PCPA(ABSTRACT TRUNCATED AT 250 WORDS)