The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

• Published in: British journal of pharmacology 2013-05, Vol.169 (2), p.426-436
• Main Authors: Eans, Shainnel O, Ganno, Michelle L, Reilley, Kate J, Patkar, Kshitij A, Senadheera, Sanjeewa N, Aldrich, Jane V, McLaughlin, Jay P
• Format: Article
• Language: English
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer - pharmacology; Administration, Oral; Animals; antagonist; antinociception; Behavior, Animal - drug effects; Blood-Brain Barrier - metabolism; CJ‐15; cocaine; Cocaine - administration & dosage; conditioned place preference; Conditioning (Psychology) - drug effects; cyclic tetrapeptide; Dose-Response Relationship, Drug; Drug-Seeking Behavior - drug effects; Extinction, Psychological - drug effects; Injections, Subcutaneous; kappa opioid receptor; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; p.o. activity; Peptides, Cyclic - administration & dosage; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - pharmacology; Receptors, Opioid, kappa - antagonists & inhibitors; Research Papers; Time Factors; Tissue Distribution
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12132

Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)‐selective antagonist [D‐Trp]CJ‐15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D‐Trp]CJ‐15,208 s.c. or p.o. before administration of the KOR‐selective agonist U50,488 and the determination of antinociception in the warm‐water tail‐withdrawal assay. The locomotor activity of mice treated with [D‐Trp]CJ‐15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D‐Trp]CJ‐15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D‐Trp]CJ‐15,208 administered s.c. or p.o. dose‐dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm‐water tail‐withdrawal assay for less than 12 and 6 h respectively. [D‐Trp]CJ‐15,208 also produced limited (