title: Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions.
abstract: We have shown previously that D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) produces selective antagonism of mu, but not delta or kappa, opioid receptor-selective ligands in the guinea pig ileum and mouse vas deferens bioassays, and in radioligand binding assays using homogenized rat brains. In the present study we characterized the agonist and opioid antagonist profile of CTP in analgesic (hot-plate test, abdominal stretch test) and in gastrointestinal assays (transit time test) in mice. CTP was a potent antagonist of the supraspinal and spinal analgesic effects of the mu selective agonist [MePhe3, D-Pro4]morphiceptin (PL017) in both assays. The gastrointestinal antitransit actions of PL017 were also antagonized by CTP at both supraspinal and spinal sites. CTP did not alter the effects of the kappa agonist trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)cyclohexyl)benz eneacetamine in any test. Surprisingly, CTP also antagonized the analgesia produced by i.c.v. and intrathecal administration of [D-Pen2, D-Pen5]enkephalin (DPDPE), a highly delta selective agonist, in both analgesic tests. Differential antagonism of DPDPE, but not PL017, by the delta selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH in the hot-plate test indicates that PL017 and DPDPE may act at separate receptors to produce analgesia (mu and delta, respectively). In contrast, CTP did not reverse the gastrointestinal antitransit effects of intrathecal DPDPE. Schild analysis of the interactions of CTP with supraspinal mu and delta agonists in the hot-plate test indicated that although CTP antagonized PL017 in a competitive fashion (Schild slope = -1.0), the interaction of CTP with DPDPE was not competitive (Schild slope = -0.5).(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000037:antagonists & inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004723:Endorphins / Q000037:antagonists & inhibitors; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000037:antagonists & inhibitors; D005769:Gastrointestinal Motility / Q000187:drug effects; D006358:Hot Temperature; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017450:Receptors, Opioid, mu; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009270:Naloxone; D013004:Somatostatin; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-; C051868:phenylalanyl-cyclo(cysteinyl-tyrosyltryptophyl-lysyl-threonyl-penicillamine)threoninamide