F. Betoin et al., EVIDENCE FOR A CENTRAL LONG-LASTING ANTINOCICEPTIVE EFFECT OF VAPREOTIDE, AN ANALOG OF SOMATOSTATIN, INVOLVING AN OPIOIDERGIC MECHANISM, The Journal of pharmacology and experimental therapeutics, 269(1), 1994, pp. 7-14
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.