The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats.
The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats.
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卡帕 - 阿片受体激动剂Nalfurafine阻止了羟考酮自我给药和羟考酮对雄性大鼠的条件奖励作用。
DOI：
10.1097/fbp.0000000000000581
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发表时间：
2020-12
影响因子：
1.6
通讯作者：
Freeman KB
中科院分区：
文献类型：
--
作者：
Zamarripa CA;Patel TR;Williams BC;Pareek T;Schrock HM;Prisinzano TE;Freeman KB
μ-阿片受体（莫尔）激动剂对于疼痛的治疗是高度有效的，但具有显著的滥用倾向。最近，我们报道了纳呋拉芬，当与羟考酮以一定的比例组合时，减少羟考酮在大鼠中的增强作用，同时产生附加的抗伤害性作用。然而，问题仍然存在，包括1）如果该组合将作为药物初治大鼠的一种药物，以及2）如果该组合产生了可以解释纳呋拉芬减少羟考酮自我给药的能力的令人厌恶的作用？在本研究中，我们研究了纳呋拉芬在未用药大鼠中以混合物形式自我给药时减少羟考酮自我给药的能力。此外，我们研究了纳呋拉芬减弱羟考酮诱导的条件性位置偏爱（CPP）的能力。在自我给药研究中，雄性Sprague-Dawley（SD）大鼠（n=8/组）在固定比例强化方案下自我静脉注射羟考酮（0.056 mg/kg/注射）、羟考酮/纳呋萘芬复方制剂（0.056/0.0032 mg/kg/注射）或生理盐水20天，以比较获得药物摄取的速率。在CPP试验中，雄性SD大鼠（n=12只/组）接受生理盐水、羟考酮（3.2 mg/kg）、纳呋拉芬（0.18 mg/kg）或羟考酮/纳呋拉芬联合给药，其比例与自我给药研究中使用的比例相同（3.2 mg/kg/0.18 mg/kg）。所有自我给予羟考酮单独给药的受试者均符合采集标准。然而，仅13%的羟考酮/纳呋拉芬自我给药受试者符合标准，无受试者获得生理盐水自我给药。在CPP试验中，羟考酮在大鼠中产生了奖励作用，而纳呋拉芬单独给药以及与羟考酮联合给药未产生显著作用。这些结果表明，与单用羟考酮相比，羟考酮和纳呋拉芬联合用药在阿片类初治患者中的习惯形成较少。
Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including 1) if the combination will function as a reinforcer in drug-naïve rats, and 2) if the combination produces aversive effects that could explain nalfurafine’s ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine’s ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats. In addition, we investigated nalfurafine’s ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley (SD) rats (n=8/group) self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male SD rats (n=12/group) received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13 % of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone produced rewarding effects in rats in the CPP test while nalfurafine alone and as a combination with oxycodone produced no significant effects. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.