Thousands of individuals die each year from opioid-related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high-dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal-cNPs) on morphine-induced antinociception in the hotplate test. We found that Nal-cNP treatment blocked the antinociceptive effect of morphine within 15 min of administration. Next, we tested the impact of Nal-cNPs on POW symptoms in male morphine-dependent mice. To induce morphine dependence, mice were treated with 5 mg/kg morphine (or saline) twice-daily for six consecutive days. On day 7 mice received 5 mg/kg morphine (or saline) injections 2 hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal-cNP, empty nanoparticle (cNP-empty), or saline. Behavior was analyzed for 0–6 hr followed by 24 and 48 hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine-dependent mice compared to saline-treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal-cNP. Side effects of Nal-cNP on locomotion and fecal boli production were measured and no significant side-effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine-dependent mice.

中文翻译：

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纳洛酮的缓慢持续递送降低了雄性吗啡依赖小鼠中典型的纳洛酮诱导的沉淀阿片类药物戒断作用

每年有数千人死于与阿片类药物相关的过量服用。虽然纳洛酮 (Narcan®) 是目前使用最广泛的逆转阿片类药物毒性的治疗方法，但这种解毒剂的高剂量或重复剂量通常会导致阿片类药物戒断 (POW)。我们假设与高剂量游离纳洛酮相比，纳洛酮从纳米颗粒中缓慢线性释放会导致更少的 POW 症状。首先，我们在热板试验中测量了共价纳洛酮纳米颗粒 (Nal- c NPs) 对吗啡诱导的抗伤害感受的急性影响。我们发现 Nal- c NP 治疗在给药后 15 分钟内阻断吗啡的镇痛作用。接下来，我们测试了 Nal- c的影响NPs 对雄性吗啡依赖小鼠的 POW 症状。为了诱导吗啡依赖，连续六天每天两次用 5 mg/kg 吗啡（或盐水）治疗小鼠。在第 7 天，小鼠在接受未修饰的游离纳洛酮、高剂量或低剂量的 Nal- c NP、空纳米颗粒 ( c NP-empty) 或盐水治疗前 2 小时接受 5 mg/kg 吗啡（或盐水）注射。行为分析 0-6 小时，然后是治疗后 24 小时和 48 小时的时间点。正如预期的那样，与使用游离纳洛酮的盐水处理小鼠相比，游离纳洛酮导致吗啡依赖小鼠的 POW 行为显着增加。相比之下，两种剂量的 Nalc NP 均观察到 POW 行为减少。Nal- c的副作用测量了 NP 对运动和粪便产生的影响，没有观察到明显的副作用。总体而言，我们的数据表明，从共价纳米颗粒持续释放纳洛酮不会在吗啡依赖小鼠中引起严重的 POW 症状。