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

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.