Opioid inhalation in mice as a model to investigate biological drivers of the opioid crisis

Opioid overdoses claim the lives of more than 100,000 Americans annually, and most of them involve synthetic opioids, such as fentanyl [cdc.gov]. Opioids have been historically used by inhalation, from opium dens to black tar heroin smoking, known as “chasing the dragon.” Recent studies show that humans with opioid use disorder (OUD) are switching from injecting to smoking fentanyl [1] due to injection difficulties and the fear of overdose.

The wide availability of behaviorally selected and transgenic mouse lines that allow for brain region- and cell type-specific manipulations constitute powerful tools for investigations of the biological mechanisms of opioid addiction. Although intravenous opioid self-administration in mice has been used successfully, its use remains scarce because of the difficulty of vein catheterization and high failure rates of catheter patency [2].

To overcome these challenges with intravenous drug self-administration, we modified a rat model [3] and developed a mouse model of vaporized fentanyl self-administration [4]. We showed that mice readily self-administered fentanyl vapor, titrated their drug intake, and achieved blood fentanyl concentrations that produce pharmacological effects. Compared with mice that were allowed limited access (nondependent), male and female mice that were allowed extended access (dependent) to fentanyl vapor exhibited greater addiction-like behaviors, such as escalated drug intake, greater motivation to wait or to work to obtain fentanyl, drug intake despite punishment, and the development of hyperalgesia and somatic signs of withdrawal [5]. Although we did not observe overall differences between the dependent and non-dependent groups on blood chemokine and cytokine levels, we found correlations between blood levels of chemokine ligand 4 (CCL-4), tumor necrosis factor α (TNF-α), and interleukin-17 (IL-17) with addiction-like behaviors in dependent but not nondependent mice, suggesting that peripheral cytokines and chemokines could serve as markers of addiction severity [5]. These preliminary findings are exciting when considering the evidence of pro-inflammatory states in OUD [6], but additional studies are required to determine causality.

Vapor self-administration models have advantages relative to intravenous self-administration models, such as (1) indwelling catheters do not need to be surgically implanted, with no subsequent need to recover from surgery, (2) vapor models are not subject to catheter failure, thus allowing longitudinal studies, (3) vapor models allow drug choice experiments without the need for dual catheterization, and (4) vapor models avoid tether entanglement if combined with other techniques, such as optogenetics and calcium imaging, which require a tether. However, vapor self-administration models also have caveats, such as (1) it is difficult to precisely calculate levels of drug exposure, (2) larger amounts of drug are needed (i.e., most drug vapor goes to waste), and (3) the system requires filters and air compressors connected to the facility exhaust to ensure the safety of experimenters (Fig. 1).

Fig. 1.

Advantages and disadvantages of operant fentanyl self-administration in mice.

Combining advanced neuroscience techniques with prolonged access to fentanyl vapor self-administration presents a unique opportunity for in-depth investigations of the biological bases of OUD, including changes in immune systems as potential markers of addiction severity. This approach will contribute to discoveries that are crucial to improve prevention, diagnosis, and treatment strategies for OUD.

Author contributions

RCNM and LFV wrote and edited the manuscript.

Funding

This work was supported by National Institutes of Health funding (ZIA-DA000602, National Institute on Drug Abuse, Intramural Research Program, Neurobiology of Addiction Section, PI: George Koob; ZIA-DA000644, National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Stress and Addiction Neuroscience Unit, PI: LFV). RCNM received funding from the Center on Compulsive Behaviors, National Institutes of Health, via the National Institutes of Health Shared Resource Subcommittee and a Pathway for Independence Award (1K99DA056618-01A1) from the National Institute on Drug Abuse.

Competing interests

The authors declare no competing interests.