The
opioid receptor antagonist properties of four conformationally constrained cyclic octapeptide analogues of
somatostatin were investigated using in vitro functional paradigms of mu-, delta- and
kappa-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (
CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-
Tic-
CTOP (TCTOP) and D-
Tic-CTAP (
TCTAP). Activation of
mu-receptors by the
enkephalin analogue Tyr-D-
Ala-Gly-(NMe)
Phe-Gly-ol (
DAGO) inhibited the (electrically evoked) release of [3H]
noradrenaline (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values:
CTOP and CTAP 7.9-8.0, TCTOP and
TCTAP 8.7-8.8). Selective activation of
kappa-opioid receptors by the cyclohexylbenzeneaceamide U69593 (0.02 microM) inhibited (by 40-45%) the release of [3H]
dopamine (DA) from striatal slices, whereas selective activation of
delta-opioid receptors by [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (
DSTBULET; 0.1 microM) caused an inhibition (by 38-46%) of striatal [14C]
acetylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 microM
DAGO on cortical [3H]NA release. Thus, the cyclic octapeptide
somatostatin analogues
CTOP, CTAP, TCTOP and
TCTAP are potent and highly selective antagonists at the
mu-opioid receptors mediating presynaptic inhibition of NA release in the brain. The
mu-receptor affinity of the most potent of these antagonists, TCTOP and
TCTAP, appears to be similar to that of
naloxone but these antagonists have a much greater selectivity than the latter.