Non-opioid antinociceptive effects of supraspinal histogranin and related peptides: possible involvement of central dopamine D-2 receptor

The antinociceptive effects of intracerebroventricular (ICV) administration of histogranin (HN) and related peptides were assessed in the mouse writhi ng 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 t he following order for other peptides: HN-(7-15) < histone H4-(86-100) <app roximate to> HN approximate to HN-(7-10)<[Ser(1)]H- < osteogenic growth pep tide (OGP) approximate to HN-(1-10). HN-(6-9) and HN-(8-10) did not show an y 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 d emonstrated by the prolonged effects of HN and [Ser(1)]HN ( approximate to 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) w as 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/mo use) receptor antagonists, but it was significantly antagonized by the coin jection 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, an d was partially blocked by the coadministration of raclopride (1 nmol/mouse ), but not naloxone (2 nmol/mouse). In the mouse rotarod assay, relative hi gh doses (75-100 nmol/mouse) of HN and related peptides did not significant ly affect motor coordination. These results indicate that supraspinal admin istration of HN and related peptides induce significant non-opioid analgesi c effects devoid of motor activity by a mechanism that involves the partici pation of central dopamine D-2 receptors. (C) 2000 Elsevier Science Inc. Al l rights reserved.