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The macrocyclic tetrapeptide [ D ‐ T rp] CJ ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration
Author(s) -
Eans Shainnel O,
Ganno Michelle L,
Reilley Kate J,
Patkar Kshitij A,
Senadheera Sanjeewa N,
Aldrich Jane V,
McLaughlin Jay P
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12132
Subject(s) - tetrapeptide , antagonism , receptor , opioid , pharmacology , chemistry , medicine , peptide , biochemistry
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 ‐ T rp] 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 ‐ T rp] CJ ‐15,208 s.c. or p.o. before administration of the KOR ‐selective agonist U 50,488 and the determination of antinociception in the warm‐water tail‐withdrawal assay. The locomotor activity of mice treated with [ D ‐ T rp] 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 ‐ T rp] 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 ‐ T rp] CJ ‐15,208 administered s.c. or p.o. dose‐dependently antagonized the antinociception induced by i.p. administration of U 50,488 in mice tested in the warm‐water tail‐withdrawal assay for less than 12 and 6 h respectively. [ D ‐ T rp] CJ ‐15,208 also produced limited (<25%), short‐duration antinociception mediated through KOR agonism. Orally administered [ D ‐ T rp] CJ ‐15,208 dose‐dependently antagonized centrally administered U 50,488‐induced antinociception, and prevented stress‐, but not cocaine‐induced, reinstatement of extinguished cocaine‐seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. Conclusions and Implications The macrocyclic tetrapeptide [ D ‐ T rp] CJ ‐15,208 is a short‐duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [ D ‐ T rp] CJ ‐15,208 as potentially useful therapeutics.