title: Antagonist activity of the cyclic somatostatin analogue CTP at mu- but not delta- and kappa-opioid receptors involved in presynaptic inhibition of neurotransmitter release.
abstract: In the present study the opioid receptor antagonist properties of the conformationally constrained cyclic octapeptide D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), which is derived from somatostatin, were investigated, using in vitro functional paradigms of central mu-, delta- and kappa-opioid receptors. Activation of mu-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 kappa-opioid receptors by bremazocine selectively inhibited (by 45-50%) the release of [3H]dopamine (DA) from striatal slices, whereas activation of delta-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 mu-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.
authors.affiliation: Department of Pharmacology, Free University Medical Faculty, Amsterdam, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Mulder
authors.forename: G
authors.initials: G
authors.lastname: Wardeh
authors.forename: W
authors.initials: W
authors.lastname: Kazmierski
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D002250:Carbon Radioisotopes; D018377:Neurotransmitter Agents; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013004:Somatostatin; C051868:phenylalanyl-cyclo(cysteinyl-tyrosyltryptophyl-lysyl-threonyl-penicillamine)threoninamide