A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats
A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats
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DOI：
10.1124/jpet.118.253674
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发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Pravetoni, Marco
中科院分区：
文献类型：
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作者：
Raleigh, Michael D.;Baruffaldi, Federico;Pravetoni, Marco
芬太尼是一种非常有效的合成阿片类药物，越来越多地被用于掺入海洛因、可卡因和假冒处方药，导致美国、加拿大和欧洲阿片类药物导致的致命过量增加。针对芬太尼的疫苗可以在娱乐吸毒者和其他有意外接触风险的职业中提供保护，免受芬太尼的毒性影响。本研究致力于以芬太尼为基础的半抗原(F)与锁孔斑状血蓝蛋白(KLH)载体蛋白或GMP级KLH亚单位(SKLH)结合的疫苗的研制。与对照组相比，小鼠和大鼠的F-KLH免疫减少了芬太尼诱导的热板抗伤害反应，并且在大鼠中减少了芬太尼在脑中的分布。F-KLH不减弱等剂量海洛因或羟考酮对大鼠的镇痛作用。为了评估疫苗对芬太尼毒性的影响，用F-sKLH或未结合的sKLH免疫的大鼠暴露于皮下增加剂量的芬太尼。接种F-sKLH使芬太尼诱导的抗伤害作用和呼吸抑制的剂量-反应曲线右移。纳洛酮逆转了两组的芬太尼效应，表明其逆转呼吸抑制的能力被保留下来。这些数据证明了芬太尼疫苗的临床前选择性和有效性，并表明疫苗可能为减少芬太尼引起的副作用提供了一种治疗选择。
Fentanyl is an extremely potent synthetic opioid that has been increasingly used to adulterate heroin, cocaine, and counterfeit prescription pills, leading to an increase in opioid-induced fatal overdoses in the United States, Canada, and Europe. A vaccine targeting fentanyl could offer protection against the toxic effects of fentanyl in both recreational drug users and others in professions at risk of accidental exposure. This study focuses on the development of a vaccine consisting of a fentanyl-based hapten (F) conjugated to keyhole limpet hemocyanin (KLH) carrier protein or to GMP-grade subunit KLH (sKLH). Immunization with F-KLH in mice and rats reduced fentanyl-induced hotplate antinociception, and in rats reduced fentanyl distribution to the brain compared with controls. F-KLH did not reduce the antinociceptive effects of equianalgesic doses of heroin or oxycodone in rats. To assess the vaccine effect on fentanyl toxicity, rats immunized with F-sKLH or unconjugated sKLH were exposed to increasing subcutaneous doses of fentanyl. Vaccination with F-sKLH shifted the dose-response curves to the right for both fentanyl-induced antinociception and respiratory depression. Naloxone reversed fentanyl effects in both groups, showing that its ability to reverse respiratory depression was preserved. These data demonstrate preclinical selectivity and efficacy of a fentanyl vaccine and suggest that vaccines may offer a therapeutic option in reducing fentanyl-induced side effects.