The antinociceptive effects of intracerebroventricular (ICV) administration of histogranin (HN) and related peptides were assessed in the mouse writhing and tail-flick assays. In the writhing test, the peptides displayed dose-dependent analgesic effects with an AD(50) of 23.9 nmol/mouse for HN and the following order for other peptides: HN-(7-15)<histone H4-(86-100) approximately HN approximately HN-(7-10)<[Ser(1)]HN<osteogenic growth peptide (OGP) approximately HN-(1-10). HN-(6-9) and HN-(8-10) did not show any significant analgesic activity at 50 nmol/mouse. The importance of the C- and N-terminal amino acids in the analgesic activity of the peptides was demonstrated by the prolonged effects of HN and [Ser(1)]HN ( approximately 30 min) compared with those of HN fragments (HN-(7-15), HN-(1-10) and HN-(7-10): 5-10 min). The analgesic activity of [Ser(1)]HN (50 nmol/mouse) was not affected by the coadministration of opioid (naloxone, 1 nmol/mouse), NMDA (CPP, 0.3 and MK-801, 0.3 nmol/mouse) and D(1) (SCH-23390, 0.5 nmol/mouse) receptor antagonists, but it was significantly antagonized by the coinjection of the D(2) receptor antagonist raclopride (0.5 nmol/mouse). In the mouse tail-flick assay, HN and related peptides (50 nmol/mouse) also showed significant analgesic activity (15-35% MPE). The analgesic effect of [Ser(1)]HN was dose-dependent and, at 75 nmol/mouse, lasted for up to 45 min, and was partially blocked by the coadministration of raclopride (1 nmol/mouse), but not naloxone (2 nmol/mouse). In the mouse rotarod assay, relative high doses (75-100 nmol/mouse) of HN and related peptides did not significantly affect motor coordination. These results indicate that supraspinal administration of HN and related peptides induce significant non-opioid analgesic effects devoid of motor activity by a mechanism that involves the participation of central dopamine D(2) receptors.