Female rats self-administer heroin by vapor inhalation

Abstract

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48 h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.

Keywords: Anti-nociception; E-cigarette; Opioids; Reinforcement; Vape.

Figure 1

Mean (N=16; ±SEM) tail-withdrawal latencies following (top) s.c. injection or (bottom) inhaled routes of administration for heroin, oxycodone or methadone. A significant difference from vehicle (Saline or PG, respectively) at a given time point is indicated with *, from oxycodone (2 mg/kg or 100 mg/mL) with #, from methadone with $, from Heroin with &, and from all other treatment conditions with %.

Figure 2:

Mean (N=16; ±SEM) A) reinforcers obtained (30 sec epochs of vapor delivery), and B) lever discrimination ratios exhibited, for one-hour heroin vapor self-administration sessions in female rats. Data are presented for High and Low responder sub-groups in panels C and D. Significant differences between HR and LR groups are indicated by *. Significant differences from session 1 and session 2 are indicated by # and &, respectively.

Figure 3:

Mean (±SEM) reinforcer deliveries (A, B) and time-out drug-associated lever responding (C, D) for High (A, C) and Low (B, D) Responder sub-groups. A significant difference between concentrations is indicated with *.

Figure 4:

Mean (±SEM) reinforcers obtained by HR (A; N=4) and LR (B; N=4) sub-groups of Cohort 2 following i.p. naloxone injection. A significant difference between pre-treatment conditions is indicated with *.

Figure 5:

Mean (±SEM) tail withdrawal latency for A) Cohorts 1 and 2 (N=16); B) Cohort 2 (N=8) rats before and after a 30 min heroin vapor session; C) Correlation of individual (N=8) withdrawal latency with the number of reinforcers obtained in the prior self-administration session for the 30 min vapor inhalation experiment; D) Male Wistar (N=17) rats trained in intravenous heroin self-administration and assessed before and after the session. A significant difference between assessments is indicated with *.

Figure 6:

Mean (N=8; ±SEM) time spent in A) closed and B) open arms, and number of entries into the C) closed and D) open arms of the elevated plus maze. A significant difference from the post-session assessment, is indicated with *.