The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination,Psychopharmacology

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The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination
Psychopharmacology ( IF 3.5 ) Pub Date : 2023-12-30 , DOI: 10.1007/s00213-023-06524-2
Justin N Siemian ₁ , Kristen Woodhouse ₁ , David H Liu ₂ , Yanan Zhang ₃ , Jun-Xu Li ₁

Affiliation

Rationale

Increasing evidence shows that imidazoline I₂ receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I₂ receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I₂ receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I₂ receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats.

Objectives

The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I₂ receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine.

Results

2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine.

Conclusions

These results suggest that I₂ receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I₂ receptor agonist-opioid combination therapy for pain control.

中文翻译：

咪唑啉 I2 受体激动剂 2-BFI 可降低吗啡的滥用相关影响：自我给药和药物鉴别

理由

越来越多的证据表明，咪唑啉 I₂ 受体激动剂可增强阿片类药物诱导的镇痛作用，表明 I₂ 受体激动剂与阿片类药物的组合可能是控制疼痛的有利策略。然而，I₂ 受体激动剂对阿片类药物滥用易感性的影响尚不清楚。本研究检查了 I₂ 受体激动剂 2-BFI 对大鼠阿片类药物吗啡的一些滥用相关行为影响的影响。

目标

von Frey 细丝试验用于确定 2-BFI（静脉注射，静脉注射）在完全弗氏佐剂（CFA）诱导的炎症性疼痛大鼠模型中的抗伤害作用。IV 自我给药用于评估单独 2-BFI 的增强作用，并评估非或有注射 2-BFI （ip）对吗啡自我给药的影响。使用双杠杆药物鉴别范式，其中训练大鼠区分 3.2 mg/kg 吗啡（ip）与盐水，以检查 2-BFI 或其他 I₂ 受体激动剂 2-（4,5-二氢咪唑-2-基）盐酸喹啉（BU224）是否影响吗啡的鉴别刺激作用。