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阿片类药物维持治疗大鼠模型中慢性给予 NOP/MOR 部分激动剂 AT-201 和 NOP 拮抗剂 J-113397 对海洛因复吸的影响。

Effect of chronic delivery of the NOP/MOR partial agonist AT-201 and NOP antagonist J-113397 on heroin relapse in a rat model of opioid maintenance.

机构信息

Behavioral Neuroscience Branch, IRP/NIDA/NIH, Baltimore, MD, U.S.A..

Behavioral Neuroscience Branch, IRP/NIDA/NIH, Baltimore, MD, U.S.A.

出版信息

Psychopharmacology (Berl). 2024 Dec;241(12):2497-2511. doi: 10.1007/s00213-024-06678-7. Epub 2024 Sep 13.

DOI:10.1007/s00213-024-06678-7
PMID:39269500
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11569015/
Abstract

RATIONALE

The opioid crisis persists despite availability of effective opioid agonist maintenance treatments (methadone and buprenorphine). Thus, there is a need to advance novel medications for the treatment of opioid use and relapse.

OBJECTIVES

We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine and the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. In contrast, chronic delivery of the buprenorphine analog BU08028 had mixed effects on different heroin relapse-related measures. Here, we tested the effect of the mixed nociceptin (NOP) receptor/MOR partial agonist AT-201 and the NOP receptor antagonist J-113397 on different heroin relapse-related measures.

METHODS

We trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing AT-201 (0, 3.8, or 12 mg/kg/d) or J-113397 (0, 12.6, or 40 mg/kg/d). Next, we tested the effect of chronic delivery of the compounds 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) context A-induced reinstatement of heroin seeking, and (4) reacquisition of heroin self-administration in context A.

RESULTS

In females, AT-201 modestly increased reacquisition of heroin self-administration and J-113397 modestly decreased incubation of heroin seeking. The compounds had no effect on the other relapse-related measures in females, and no effect on any of the measures in males.

CONCLUSION

The NOP/MOR partial agonist AT-201 and the NOP antagonist J-113397 did not mimic buprenorphine's inhibitory effects on relapse in a rat model of opioid maintenance treatment.

摘要

背景

尽管有有效的阿片类激动剂维持治疗（美沙酮和丁丙诺啡），但阿片类药物危机仍在持续。因此，需要开发新型药物来治疗阿片类药物使用和复发问题。

目的

我们最近在大鼠中建立了维持治疗模型，发现丁丙诺啡和 μ 阿片受体（MOR）部分激动剂 TRV130 的慢性给药可减少对羟考酮觅药和用药的复发。相比之下，丁丙诺啡类似物 BU08028 的慢性给药对不同的海洛因复发相关措施有混合作用。在这里，我们测试了混合孤啡肽（NOP）受体/MOR 部分激动剂 AT-201 和 NOP 受体拮抗剂 J-113397 对不同海洛因复发相关措施的影响。

方法

我们训练雄性和雌性大鼠在环境 A 中自我注射海洛因（6 小时/天，14 天），然后植入含有 AT-201（0、3.8 或 12mg/kg/d）或 J-113397（0、12.6 或 40mg/kg/d）的渗透微型泵。接下来，我们测试了这些化合物的慢性给药对以下方面的影响：（1）在非药物环境 B 中海洛因觅药的潜伏期；（2）环境 B 中与海洛因相关的离散线索强化的消退反应；（3）环境 A 诱导的海洛因觅药复燃；（4）环境 A 中重新获得海洛因自我给药。

结果

在雌性大鼠中，AT-201 轻度增加了海洛因自我给药的重新获得，而 J-113397 轻度降低了海洛因觅药的潜伏期。这些化合物对雌性大鼠的其他复发相关措施没有影响，对雄性大鼠的任何措施也没有影响。

结论

NOP/MOR 部分激动剂 AT-201 和 NOP 拮抗剂 J-113397 并未在阿片类药物维持治疗的大鼠模型中模拟丁丙诺啡对复发的抑制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/cce26d0c68c3/213_2024_6678_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/e82c383a947d/213_2024_6678_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/e9deb2c2441c/213_2024_6678_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/3668bbe1630a/213_2024_6678_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/fde158202870/213_2024_6678_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/96e43610a798/213_2024_6678_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/cce26d0c68c3/213_2024_6678_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/e82c383a947d/213_2024_6678_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/e9deb2c2441c/213_2024_6678_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/3668bbe1630a/213_2024_6678_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/fde158202870/213_2024_6678_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/96e43610a798/213_2024_6678_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/022e/11569015/cce26d0c68c3/213_2024_6678_Fig6_HTML.jpg

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