Effects of 6-succinylmorphine conjugated keyhole limpet hemocyanin vaccine induced antibodies on analgesic and reward response to morphine in rats

Drug abuse and addiction afflicts over 20 million Americans and has detrimental effects on society. An immunotherapeutic approach to this problem involves the development of vaccines that produce antibodies to bind the drug in circulation, preventing its diffusion through the blood-brain barrier and inhibiting the drug’s effects on the brain.  The purpose of this study was to examine the immunological and functional effects of a morphine-6-succinyl-KLH conjugate vaccine in rats. Antibody levels were measured using ELISA assays. Reward effects of morphine were analyzed using controlled place preference (CPP), and analgesic effects of morphine at various weeks after vaccination were observed using tail-flick and hotplate assays. Finally rats given a single dose of morphine were sacrificed, and morphine levels in the brain and blood were compared using gas chromatography-mass spectrometry. Competitive inhibition ELISAs determined the affinity of the vaccine-produced antibodies for morphine and morphine metabolites. Morphine specific antibodies were present at effective levels starting at 4 weeks after vaccination. Hotplate and tail-flick assays demonstrated significant decreases in morphine analgesia of vaccinated rats. CPP showed rats with high antibody levels develop a reward response to morphine. Vaccinated rats had lower levels of morphine concentrations in brain tissue. As determined by the competition assays, the vaccine-produced antibodies had greatest affinities for morphine and the active metabolites of morphine and heroin, morphine-6-β-D-glucuronide and 6-acetylmorphine. These antibodies showed a lower affinity for the inactive metabolite, morphine-3-β-D-glucuronide. These results show promise for the development of a human vaccine for the treatment of morphine and heroin addiction.