Prophylactic vaccination protects against the development of oxycodone self-administration

Abstract

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 min after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

Keywords: Oxycodone; Self-administration; Vaccine.

Figure 1.. The general vaccination strategy using an oxycodone hapten-immunoconjugate vaccine.

A) The general vaccine strategy and B) scheme of Oxy hapten synthesis and preparation of Oxy-TT and Oxy-BSA immunoconjugates. C) Surface plasmon resonance (SPR) analysis of binding interactions confirmed that the polyclonal response presented binding to free drug in Cohorts 1 and 2. D) The vaccination schedule resulted in plasma anti-Oxy antibody midpoint titers from Oxy-TT vaccinated rats. Cohort 1 and Cohort 2 are separated into Upper or Lower groups (N=5–6) with alum and CpG ODN 1826 as adjuvants as determined by ELISA. Arrows indicate when rats were vaccinated. Data are presented as means ± SEM. Plasma from control TT vaccinated rats with alum and CpG ODN 1826 as adjuvants did not contain any detectable anti-Oxy IgG titers. TW and PK indicated tail-withdrawal tests and blood-draws for pharmacokinetic analysis, respectively.

Figure 2.. Vaccination attenuates intravenous self-administration of low dose oxycodone.

Mean (±SEM) oxycodone infusions obtained by rats in A) Cohort 1 (TT; N=11 and Oxy-TT; N=12) and B) Cohort 2 (TT; N=12 and Oxy-TT; N=11). Post hoc tests: A significant difference from each of the first three sessions, across Groups is indicated with *. Cumulative percentage of each group reaching acquisition criterion (average of 7 infusions across two sessions) in C) Cohort 1 and in D) Cohort 2. Mean (±SEM) infusions obtained by the Upper and Lower (TT Lower N=5) halves of the vaccine groups in E) Cohort 1 and F) Cohort 2. Broken lines between sessions 5 & 6, 10 & 11 and 15 & 16 represent the 70 h weekend interval. Post hoc tests: In panels E and F, the grey symbols indicate a significant difference from the first three sessions within-group. Open symbols reflect significant differences from the first three sessions and between Upper and Lower halves within each vaccine group. A significant difference between vaccine Groups or between the Upper halves of each vaccine group is indicated with #.

Figure 3.. Vaccination decreases motivation for oxycodone self-administration under increased workload.

Mean (+SEM) oxycodone infusions obtained by TT (N=11) and Oxy-TT (N=11–12) vaccinated groups in Cohort 1 under A) PR conditions or B) during a saline challenge. Post hoc tests: A significant difference within-group is indicated with * and between the groups with #. C) Training under FR1 to FR10 followed by PR challenges showed that TT (N=11) rats obtained more infusions compared to Oxy-TT (N=8) rats. Post hoc tests: A significant difference from the FR 10 (Sessions 45–63) condition is indicated with *. Mean (±SEM) infusions of oxycodone for Oxy-TT (N= 9–11) and TT (N= 11) vaccinated rats under D) PR conditions and B-C) subsequent challenges with intermittent changes in workload (PR^J2-PR^J3). Post hoc tests: A significant difference between vaccine groups for a given schedule of reinforcement condition is indicated by #, a difference from FR (0.15 mg/kg/inf) within group by * and from FR (0.06 mg/kg/inf) within group by &. ns indicates no significant difference was confirmed.

Figure 4.. Vaccination ameliorates antinociceptive effect of oxycodone.

Mean (±SEM) tail-withdrawal latency in Oxy-TT (N=12) vaccinated rats as compared to TT (N=11–12) control rats prior to and post-IVSA training in A) Cohort 1 and B) Cohort 2. C) In Cohort 1, a non-contingent injection heroin (1 mg/kg, s.c.) showed no difference between groups, but persistence of the difference after oxycodone injection (2 mg/kg, s.c.). Post hoc tests: Significant differences between the groups is indicated with #. Significant differences within group compared with Pre are indicated by * and compared with the most prior observation before a drug injection (60 or 120 min) with &.

Figure 5.. Analysis of oxycodone biodistribution in plasma and brain.

A) Mean (±SEM) oxycodone concentrations in plasma, 30 min after injection of oxycodone (1.0 mg/kg, s.c.,) in TT and Oxy-TT groups (N=11 per group) of Cohort 1. B) Mean (±SEM) oxycodone concentrations in plasma at 15 or 30 min after injection of oxycodone (1.0 or 2.0 mg/kg, s.c.) in TT (N=10) and Oxy=TT (N=11; blood could not be obtained from one animal in this experiment) groups of Cohort 2. The insert shows that TT plasma levels at 30 min were twice as high after 2 mg/kg injected versus 1 mg/kg. C) Mean (±SEM) oxycodone concentrations in whole brain tissue at 30 min after injection of oxycodone (1.0 mg/kg, s.c.) in TT (N=10) and Oxy-TT (N=11) groups of Cohort 2. At the end of study in Cohort 1 (Week 29), D) plasma oxycodone levels were significantly higher in OxyTT rats compared to TT (N=5–6) rats 30 min after an injection of oxycodone (1.0–2.0 mg/kg, s.c.), whereas E) brain oxycodone levels showed no difference between OxyTT and TT rats. Post hoc tests: A significant difference between vaccine Groups is indicated with *.