EVIDENCE FOR A CENTRAL LONG-LASTING ANTINOCICEPTIVE EFFECT OF VAPREOTIDE, AN ANALOG OF SOMATOSTATIN, INVOLVING AN OPIOIDERGIC MECHANISM

The antinociceptive effect of the octapeptide vapreotide, an analog of somatostatin, was studied after systemic injection in normal mice usi ng the hot plate and abdominal stretching assays, and in normal rats u sing the paw pressure analgesiometric assay. Vapreotide was ineffectiv e at 1 mu g/kg s.c. in the hot plate test in mice, but 30 min after in jection it induced an antinociceptive effect at s.c. injected doses of 8, 64, 512 and 4096 mu g/kg, with an ED(50) of 213 +/- 5 mu g/kg. For the three highest doses this effect persisted 24 hr after the injecti on (maximal increase: +80 +/- 23% for 512 mu g/kg) and disappeared at 48 hr. In the phenylbenzoquinone stretching test, in mice, the ED(50) was 186 +/- 6 mu g/kg (maximal decrease: -63 +/- 5%); the effect persi sted 24 hr only for the same two highest doses. Using the paw pressure test, in rats, a dose-dependent increase in paw withdrawal and vocali zation thresholds was observed for 21 and 24 hr, respectively, after s .c. injections of 16, 64 and 512 mu g/kg. Global scores obtained for v ocalization thresholds were significantly increased (vs. paw withdrawa l thresholds) for 64 and 512 mu g/kg. Carrageenan-induced nociception in rats was reduced for 21 hr by 64 and 512 mu g/kg s.c.; scores of th e contralateral noninflamed paw were also increased. Vapreotide admini stered locally in the inflamed paw was inactive. No change in edema vo lume was obtained after systemic injection of vapreotide. This suspect ed central effect was confirmed by the inhibition by naloxone of the e ffect of vapreotide in the paw pressure test in rats throughout the du ration of the action (either 2 or 18 hr after the injection of vapreot ide). Binding studies showed the ability of vapreotide to displace (H- 3)-DAMGO binding to mu opioid receptors with a higher IC50 (1.3 +/- 0. 1 x 10(-6) M) than morphine (0.8 +/- 0.3 x 10(-8) M) and octreotide (2 .5 +/- 0.6 x 10(-8) M); the IC50 of somatostatin was (2.1 +/- 0.2 x 10 (-5) M). This low affinity for mu receptors was decreased when Na+ (10 0 mM) was added. The IC50 ratio +Na+/-Na+ = 3 suggested a mixed agonis t-antagonist property, whereas octreotide is known to possess an antag onist activity on the same receptors. However, the low IC50 of vapreot ide is at variance with a direct effect of the low active doses on mu receptors. All these results demonstrate a long-lasting antinociceptiv e effect of vapreotide regardless of the species, the test and the sti mulus used. This action is not peripheral and involves a central indir ect opioidergic mechanism with spinal and supraspinal components. The demonstrated lack of effect on motor activity and of change in spinal tissue of mice and rats confirms the specificity of the behavioral res ults obtained. These data suggest a potential interest for therapeutic use in humans.