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Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine‐seeking behaviour
Author(s) -
BriceTutt Ariana C.,
Wilson Lisa L.,
Eans Shainnel O.,
Stacy Heather M.,
Simons Chloe A.,
Simpson Grant G.,
Coleman Jeremy S.,
Ferracane Michael J.,
Aldrich Jane V.,
McLaughlin Jay P.
Publication year - 2020
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.15165
Subject(s) - pharmacology , tetrapeptide , opioid , opioid receptor , agonist , chemistry , receptor antagonist , (+) naloxone , antagonist , receptor , morphine , stereochemistry , medicine , biochemistry , peptide
Background and Purpose The macrocyclic tetrapeptide natural product CJ‐15,208 ( cyclo [Phe‐ d ‐Pro‐Phe‐Trp]) is a multifunctional μ‐opioid receptor and κ‐opioid receptor agonist and κ‐opioid receptor antagonist that produces antinociception and prevents stress‐induced reinstatement of extinguished cocaine‐conditioned place preference (CPP). We hypothesized that an analogue of CJ‐15,208, cyclo [Pro‐Sar‐Phe‐ d ‐Phe], would demonstrate multifunctional μ‐opioid receptor and κ‐opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective μ‐opioid receptor agonists, while preventing both drug‐ and stress‐induced reinstatement of morphine‐induced CPP. Experimental Approach The opioid receptor agonist and antagonist activity of cyclo [Pro‐Sar‐Phe‐ d ‐Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor “knockout” mice using the 55°C warm‐water tail‐withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo [Pro‐Sar‐Phe‐ d ‐Phe] to block morphine‐ and stress‐induced reinstatement of extinguished CPP was determined. Key Results cyclo [Pro‐Sar‐Phe‐ d ‐Phe] demonstrated dose‐dependent, short‐lasting antinociception, with an ED 50 (and 95% confidence interval) of 0.15 (0.05–0.21) nmol i.c.v. and 1.91 (0.40–3.54) mg·kg −1 i.p., mediated by μ‐ and κ‐opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose‐dependent κ‐opioid receptor antagonist‐like activity at 2.5, but not at 4.5, h after administration. cyclo [Pro‐Sar‐Phe‐ d ‐Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ‐receptors. Pretreatment with cyclo [Pro‐Sar‐Phe‐ d ‐Phe] prevented stress‐ and drug‐induced reinstatement of extinguished morphine‐place preference responses in a time‐dependent manner. Conclusions and Implications These data suggest that cyclo [Pro‐Sar‐Phe‐ d ‐Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug‐ and stress‐induced relapse in morphine‐abstinent subjects.