Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and alleviate opioid tolerance and dependence. Our present studies in male Sprague-Dawley rats assessed the abuse potential of oxycodone+ultra-low-dose naltrexone (NTX) versus oxycodone alone. The lowest NTX dose (1 pg/kg/infusion), but not slightly higher doses (10 and 100 pg/kg/infusion), enhanced oxycodone (0.1 mg/kg/infusion) intravenous self-administration, suggesting a reduced rewarding potency per infusion. During tests of reinstatement performed in extinction conditions, co-self-administration of any of these three NTX doses significantly reduced drug-seeking precipitated by priming injections of oxycodone (0.25 mg/kg, s.c.), a drug-conditioned cue, or foot-shock stress. During self-administration on a progressive-ratio schedule, animals self-administering oxycodone (0.1 mg/kg/infusion)+NTX (1 pg/kg/infusion) reached a "break-point" sooner and showed a trend toward less responding compared to rats self-administering oxycodone alone (0.1 mg/kg/infusion). In the final experiment, the addition of ultra-low-dose NTX (10 pg/kg, s.c.) enhanced the acute stimulatory effect of oxycodone (1 mg/kg, s.c.), as well as locomotor sensitization produced by repeated oxycodone administration (7 x 1 mg/kg, s.c.). In summary, this work shows that ultra-low-dose NTX co-treatment augments the locomotor effects of oxycodone as it enhances opioid analgesia, but reduces oxycodone's rewarding potency and subsequent vulnerability to relapse.
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机译：超低剂量的阿片类药物拮抗剂已显示出可增强阿片类药物的镇痛作用并减轻阿片类药物的耐受性和依赖性。我们目前在雄性Sprague-Dawley大鼠中的研究评估了羟考酮+超低剂量纳曲酮（NTX）与仅羟考酮的滥用潜力。最低NTX剂量（1 pg / kg /输注），但不稍高剂量（10 pg / kg和100 pg / kg /输注），增强的羟考酮（0.1 mg / kg /输注）静脉内自我给药，表明每单位剂量的奖励效力降低输液。在灭绝条件下进行的恢复测试期间，这三种NTX剂量中的任何一种的共同自我给药可显着减少通过初次注射羟考酮（0.25 mg / kg，sc），药物条件提示或足底注射而沉淀的药物寻求。冲击压力。在以渐进比例进行自我给药的过程中，动物自我给药羟考酮（0.1 mg / kg /滴注）+ NTX（1 pg / kg /滴注）较早达到“突破点”，并显示出反应较弱的趋势。单独给予羟考酮的大鼠（0.1毫克/千克/滴注）。在最终实验中，添加超低剂量NTX（10 pg / kg，sc）增强了羟考酮（1 mg / kg，sc）的急性刺激作用，以及通过反复服用羟考酮而产生的运动敏化作用（7 x 1 mg / kg，sc）。总之，这项工作表明，超低剂量NTX联合治疗可增强羟考酮的运动效果，因为它可增强阿片类药物的镇痛作用，但会降低羟考酮的奖励能力和随后的复发易感性。
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