RT Journal Article SR Electronic T1 Vaccination reduces fentanyl distribution to the brain and fentanyl-induced toxicity in mice and rats: a potential role for a prophylactic vaccine against fentanyl-induced overdose JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.118.253674 DO 10.1124/jpet.118.253674 A1 Michael D. Raleigh A1 Federico Baruffaldi A1 Samantha J. Peterson A1 Morgan Le Naour A1 Theresa M. Harmon A1 Jennifer R. Vigliaturo A1 Paul R. Pentel A1 Marco Pravetoni YR 2018 UL http://jpet.aspetjournals.org/content/early/2018/11/08/jpet.118.253674.abstract AB 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 US, Canada, and Europe. A vaccine targeting fentanyl could offer protection against fatal overdoses 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 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 brain compared to controls. F-KLH did not reduce antinociceptive effects of equianalgesic doses of heroin or oxycodone in rats. To assess vaccine effect on fentanyl toxicity, rats immunized with F-sKLH or unconjugated sKLH were exposed to increasing s.c. 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 activity for reversing opioid overdose was preserved. These data demonstrate pre-clinical selectivity and efficacy of a fentanyl vaccine and suggest that vaccines may offer a therapeutic option in reducing fentanyl-induced overdoses.