Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi.
School of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
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。
