Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
Psychopharmacology (Berl). 2021 Apr;238(4):1017-1028. doi: 10.1007/s00213-020-05749-9. Epub 2021 Jan 6.
Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists.
The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats.
Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 μg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1-10 mg/kg) and nalfurafine (3.2-32 μg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32 mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3.
Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI.
These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.
需要策略来降低μ阿片受体（MOR）激动剂的滥用倾向。正在考虑的一种策略是将 MOR 激动剂与κ阿片受体（KOR）激动剂结合使用。
比较 KOR 激动剂（U50488、nalfurafine）在静脉内自我给予芬太尼（条件性给药）或作为皮下预处理（非条件性给药）的情况下对芬太尼与食物选择的影响，在雄性和雌性大鼠中。
大鼠在芬太尼（0、0.32-10μg/kg/输注）和食物强化的同时进行训练。在实验 1 中，U50488 和 nalfurafine 与芬太尼一起作为固定比例混合物（条件性给药）给药。在实验 2 中，U50488（1-10mg/kg）和 nalfurafine（3.2-32μg/kg）作为急性预处理（非条件性给药）给药。在实验 3 中，在进行条件和非条件 KOR 激动剂治疗之前，给予选择性 KOR 拮抗剂 nor-BNI（32mg/kg）。
U50488 和 nalfurafine 均在条件性给药时降低芬太尼的选择，表明 KOR 激动剂惩罚阿片类药物选择。然而，惩罚的证据与大多数大鼠的操作性反应消除相对应。非条件 U50488 和 nalfurafine 给药仅减少行为会议期间的选择次数，而不改变芬太尼的选择。nor-BNI 减弱了条件和非条件 KOR 激动剂对芬太尼选择的影响。
这些结果表明，KOR 激动剂对芬太尼强化的影响取决于它们给药的条件。
