In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia
In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia
复制标题
DOI：
10.1016/j.biopsych.2020.02.014
复制
发表时间：
2020-12-15
影响因子：
10.6
通讯作者：
Shaham, Yavin
中科院分区：
文献类型：
--
作者：
Bossert, Jennifer M.;Kiyatkin, Eugene A.;Shaham, Yavin
背景技术背景：阿片类激动剂（丁丙诺啡，美沙酮）的维持治疗对阿片类成瘾有效，但并不能消除所有患者的阿片类药物使用。我们在自我给予处方阿片类羟考酮的大鼠中建立了维持治疗模型。维持药物是丁丙诺啡或G蛋白偏向的μ阿片受体激动剂TRV 130。然后，我们测试了预防羟考酮寻求和禁欲期间使用修改后的上下文诱导的恢复程序，大鼠复发model.METHODS：我们训练大鼠自我管理羟考酮（6小时/天，14天）在上下文A;输注与离散的音调光线索配对。然后，我们植入含有丁丙诺啡或TRV 130（0、3、6或9 mg/kg/天）的渗透泵，并进行3次连续测试：在非药物背景B（消退反应）中通过羟考酮相关离散线索加强杠杆按压，在背景A中背景诱导恢复羟考酮寻求，在背景A中重新获得羟考酮自我给药。我们还测试了TRV 130的维护是否会保护急性羟考酮诱导的减少，在nucleus objectivens oxygen levels.RESULTS：在雄性大鼠中，丁丙诺啡和TRV 130减少了消退反应和重新获得羟考酮自我管理，但有一个较弱的（不显着）的影响，上下文诱导的恢复。在雌性大鼠中，丁丙诺啡降低了所有3项测试中的反应，而TRV 130仅降低了消退反应。在这两种性别，TRV 130防止急性脑缺氧诱导的中等剂量的oxycodoned.CONCLUSIONS：TRV 130减少oxycodone寻求和服用在禁欲期间的部分性别特异性的方式，并防止急性oxycodone诱导的脑缺氧。我们建议，G蛋白偏向μ阿片受体激动剂，目前正在开发的镇痛药，应被视为阿片类药物成瘾的复发预防维持治疗。
BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model.METHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels.RESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone.CONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction.