κ 阿片受体激动剂纳呋拉啡阻断雄性大鼠阿片类药物自我给药和阿片类药物条件性奖赏效应的获得。
The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats.
机构信息
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi.
School of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
出版信息
Behav Pharmacol. 2020 Dec;31(8):792-797. doi: 10.1097/FBP.0000000000000581.
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 if the combination will function as a reinforcer in drug-naïve rats, and 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 and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats 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 Sprague-Dawley rats 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, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.
μ-阿片受体（MOR）激动剂在治疗疼痛方面非常有效，但具有显著的滥用倾向。最近，我们报告称，纳呋拉啡与羟考酮以一定比例联合使用时，可降低羟考酮在大鼠中的强化作用，同时产生相加的镇痛作用。然而，仍存在一些问题，包括该联合用药在药物-naive 大鼠中是否作为一种强化物，以及该联合用药是否产生厌恶效应，从而解释纳呋拉啡降低羟考酮自我给药的能力？在本研究中，我们调查了纳呋拉啡在药物-naive 大鼠中作为混合物自我给药时，降低羟考酮自我给药获得的能力，以及纳呋拉啡降低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 大鼠在固定比率强化程序下自我注射静脉内注射羟考酮（0.056 mg/kg/注射）、羟考酮/纳呋拉啡混合物（0.056/0.0032 mg/kg/注射）或生理盐水，以比较药物摄入的获得速度。在 CPP 测定中，雄性 Sprague-Dawley 大鼠接受皮下注射生理盐水、羟考酮（3.2 mg/kg）、纳呋拉啡（0.18 mg/kg）或在自我给药研究中使用的相同比例的羟考酮/纳呋拉啡混合物（3.2 mg/kg/0.18 mg/kg）。单独接受羟考酮的所有受试者均符合获得标准。然而，只有 13%接受羟考酮/纳呋拉啡的受试者符合标准，没有受试者接受生理盐水的自我给药。羟考酮，但不是纳呋拉啡单独或羟考酮/纳呋拉啡混合物，在 CPP 测试中对大鼠产生了奖赏作用。这些发现表明，与单独使用羟考酮相比，在阿片类药物-naive 患者中，羟考酮和纳呋拉啡的联合使用不太可能形成习惯。
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