Sex differences in the effect of chronic delivery of the buprenorphine analog BU08028 on heroin relapse and choice in a rat model of opioid maintenance

Jennifer Bossert and Lindsay Altidor

Hot Off the Press – October 12, 2021

Previous studies reported that the NOP/µ receptor partial agonist BU08028 produced antinociception in rodents and non-human primates and is not self-administered by non-human primates, leading to the suggestion that BU08028 can be a promising candidate for opioid addiction treatment. In a buprenorphine-validated rat model of opioid agonist maintenance treatment, we report that chronic BU08028 delivery resulted in sex-dependent beneficial and detrimental effects on some measures of heroin relapse and sex-independent null effects on other relapse measures and heroin choice. We conclude that to the degree that our buprenorphine-validated rat models of heroin relapse and choice predict medication efficacy in humans, our results suggest that mixed NOP/µ receptor partial agonists should not be considered for the treatment of opioid addiction in humans.

Publication Information

Bossert, Jennifer M; Townsend, E Andrew; Altidor, Lindsay; Fredriksson, Ida; Shekara, Aniruddha; Husbands, Stephen; Sulima, Agnieszka; Rice, Kenner C; Banks, Matthew L; Shaham, Yavin

Sex differences in the effect of chronic delivery of the buprenorphine analog BU08028 on heroin relapse and choice in a rat model of opioid maintenance Journal Article

In: Br J Pharmacol, 2021, ISSN: 1476-5381.

Abstract | Links

@article{pmid34505281,

title = {Sex differences in the effect of chronic delivery of the buprenorphine analog BU08028 on heroin relapse and choice in a rat model of opioid maintenance},

author = {Jennifer M Bossert and E Andrew Townsend and Lindsay Altidor and Ida Fredriksson and Aniruddha Shekara and Stephen Husbands and Agnieszka Sulima and Kenner C Rice and Matthew L Banks and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/34505281/},

doi = {10.1111/bph.15679},

issn = {1476-5381},

year  = {2021},

date = {2021-09-01},

urldate = {2021-09-01},

journal = {Br J Pharmacol},

abstract = {BACKGROUND AND PURPOSE: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine or the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. Here, we tested the effect of the buprenorphine analog BU08028 on different heroin relapse-related measures and heroin vs. food choice.



EXPERIMENTAL APPROACH: For relapse assessment, we trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing BU08028 (0, 0.03, or 0.1 mg/kg/d). We then tested the effect of chronic BU08028 delivery on (1) incubation of heroin seeking in a non-drug context B, (2) extinction responding reinforced by heroin-associated discrete cues in context B, (3) reinstatement of heroin seeking induced by reexposure to context A, and (4) reacquisition of heroin self-administration in context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin vs. food choice.



RESULTS: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased reacquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin vs. food choice in both sexes. Finally, exploratory post-hoc analyses suggest that BU08028 decreased extinction responding selectively in males.



CONCLUSIONS AND IMPLICATIONS: Chronic BU08028 delivery had both beneficial and detrimental sex-dependent effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 will not be an effective opioid maintenance treatment in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}