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The relative importance of descending serotonergic and noradrenergic pathways to the antinociceptive action of supraspinally and systemically administered morphine sulfate, and to the antinociceptive synergism observed between spinally and supraspinally administered morphine was examined in mice. Morphine administered i.c.v., intrathecally (i.t.), s.c. or i.t. + i.c.v. produced a dose-dependent antinociceptive response, as measured by the tail-flick test. The dose-response curve for morphine (i.c.v.) was shifted significantly to the right by equal i.t. doses of methysergide or phentolamine. However, the most pronounced shift to the right was caused by i.t. administration of the selective alpha-2 antagonist yohimbine. Administration of a subantinociceptive dose of morphine (i.t.) along with morphine (i.c.v.) shifted the dose-response curve for morphine (i.c.v.) 6-fold to the left. The resulting dose-response curve for …