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J Pharmacol Exp Ther. 2018 Nov 8. pii: jpet.118.253674. doi: 10.1124/jpet.118.253674. [Epub ahead of print]

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.

Author information

1
Hennepin Healthcare Research Institute; rale0011@umn.edu.
2
Hennepin Healthcare Research Institute.
3
University of Minnesota.

Abstract

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.

KEYWORDS:

antinociception; behavior; drug abuse; drug toxicity; immunopharmacology; immunotherapy; morphine; opioids; pharmacokinetics; respiratory pharmacology

PMID:
30409833
DOI:
10.1124/jpet.118.253674
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