Abstract
antagonist activity would prevent both stress and drug-induced reinstatement of extinguished cocaine-seeking behavior. Methods: In mice, we tested two putative mixed opioid agonist/antagonists, (−)pentazocine and the novel cyclic tetrapeptide cyclo[Ala-d-Pro-Phe-d-Trp] (Cmpd 1), for opioid efficacy and selectivity in the 55 ◦C warm-water tail-withdrawal assay, and then determined both compounds effects on the reinstatement of cocaine in a conditioned place preference (CPP) assay. Results: (−)Pentazocine and Cmpd 1 demonstrated equivalent efficacy in the tail-withdrawal assaywith ED50 (and 95% CI) values of 2.51(1.66–4.27) and 3.03(2.16–4.58) nmol, i.c.v., respectively. However, whereas (−)pentazocine antinociception was mediated by all three opioid receptors, the antinociception of Cmpd 1 appeared to be primarily mediated by KOR, with a small contribution by MOR. Pretreatment (10 nmol i.c.v., −3h) with Cmpd 1 selectively antagonized KOR, whereas (−)pentazocine primarily antagonized DOR. Surprisingly, while pretreatment (−3h/d, i.c.v.) with either compound dose-dependently prevented a 2-day stressinduced reinstatement, acute administration of Cmpd 1 but not (−)pentazocine blocked cocaine-induced reinstatement. Conclusions: Overall, these data suggest that with its distinct activity profile, compound 1 is a promising lead compound for potential development, particularly as a therapeutic to prevent relapse to drug seeking behavior in abstinent subjects. Financial support: Funding provided by NIDA (DA023924 and DA032928) and the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development.
Published Version
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