Antagonist activity of the cyclic somatostatin analogue CTP at μ- but not δ- and κ;;-opioid receptors involved in presynaptic inhibition of neurotransmitter release

In the present study the opioid receptor antagonist properties of the confomationally constrained cyclic octapeptide D-Phe-{A figure is presented}-Thr-NH₂ (CTP), which is derived from somatostatin, were investigated, using in vitro functional paradigms of central μ-, δ- and κ-opioid receptors. Activation of μ-opioid receptors by the enkephalin analogues DADLE or DAGO resulted in a strong inhibition (by 60-70%) of the (electrically evoked) release of [³H]noradrenaline (NA) from superfused cortical slices. This inhibitory effect was antagonized by CTP in a competitive fashion (pA₂ value 7.7-7.9). Activation of κ-opioid receptors by bremazocine selectively inhibited (by 45-50%) the release of [³H]dopamine (DA) from striatal slices, whereas activation of δ-opioid receptors by DADLE caused an inhibition (by 55-60%) of striatal [¹⁴C]acetylcholine (ACh) release, but neither of these inhibitory effects was affected by CTP. By itself, CTP inhibited cortical [³H]NA release (by 35-40%), but it did not affect the release of [³H]DA nor that of [¹⁴C]ACh from striatal slices. The inhibitory effect of CTP was not antagonized by naloxone. The data indicate that CTP selectively antagonizes μ-opioid receptors, involved in presynaptic inhibition of NA release in the brain. In addition, the peptide by itself causes an inhibition of NA release via a non-opioid receptor-mediated process.