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

Abstract

Background and Purpose Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse‐related measures and heroin versus food choice. Experimental Approach For relapse assessment, we trained male and female rats to self‐administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested 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 re‐exposure to Context A and (4) re‐acquisition of heroin self‐administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re‐acquisition of heroin self‐administration selectively in females. Chronic BU08028 had minimal effects on context‐induced reinstatement and heroin versus 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 would not be an effective opioid maintenance treatment in humans.

Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder

“…There have been relatively few studies that directly compare male and female addiction-like behaviors for oxycodone self-administration in preclinical models [5,[29][30][31][32]. In our study, the effect of naltrexone in reducing motivation for oxycodone self-administration was similarly reduced in male and female HS rats.…”

“…Several studies have examined the effects of FDA approved drugs on the rewarding potency, extinction, and relapse vulnerability from opioids such as oxycodone, heroine or fentanyl [5,[14][15][16][17][18][19].…”

“…This pharmacological profile of methadone raises concerns and limits its use, as it can cause a dose-dependent decrease in respiration often associated with apnea at high doses. Buprenorphine is a long-lasting partial agonist at MOP and NOP receptors, and an antagonist at DOP and KOP receptors [4, 5]. Methadone and buprenorphine are particularly effective in reducing opioid-induced mortality and maintaining patients in treatment, but important safety concerns and strict regulations because of their agonist properties at MOPs have limited their use [6, 7].…”

Effect of selective lesions of nucleus accumbens μ-opioid receptor-expressing cells on heroin self-administration in male and female rats: a study with novelOprm1-Creknock-in rats

“…Our results suggest mechanistic differences in the role of MOR-expressing cells in heroin seeking and taking. This notion is supported by results from our recent studies on the sex-dependent effects of TRV130 (a selective partial agonist of MOR) and BU08028 (a mixed partial agonist of MOR and nociceptin/orphanin/FQ peptide receptor) on context-induced reinstatement and reacquisition of heroin and oxycodone self-administration (Bossert et al, 2020;Bossert et al, 2022). These sex-dependent effects in opioid relapse occurred even though we did not observe sex differences in opioid selfadministration in our previous studies and in the current study.…”

“…NIDA: We received heroin hydrochloride (HCl) and morphine sulfate from the NIDA pharmacy and dissolved them in sterile saline. The heroin unit doses of Experiment 2 are based on our previous work (Bossert et al, 2004;Bossert et al, 2016;Bossert et al, 2022) and the heroin unit doses in Experiment 4-5 are based on Stewart et al (1996). The morphine (1 ml/kg, s.c) doses and lactic acid (Cat #L1250, Sigma Aldrich, dissolved in sterile water) concentrations in Experiment 3 are based on Baldwin et al (Baldwin et al, 2022) and Reiner et al (Reiner et al, 2021).…”