Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

We studied the behavioral consequences of fentanyl vapor self-administration (SA) in mice with and without chronic neuropathic pain (one month after spared-nerve injury(SNI) model or sham injury). We assessed fentanyl consumption, motivation, and seeking during as well as anxiety, hyperactivity, immobility, and pain for two regimens of fentanyl SA: 1) Dose escalation, where over a 3-week period mice are exposed (daily 2-hour sessions) to escalating numbers of fentanyl puffs per active nosepoke (from 1 puff/active nosepoke for first 3 days, up to 6 puffs/active nosepoke in days 16-18). 2) Effort escalation, where over a 3-week period (daily 2-hour sessions) mice need to increase effort to acquire the same amount of fentanyl (fixed ratio 1 (FR) = 1 active nosepoke results in 1 fentanyl puff, while second and third week we use FR5 and FR10). We observe sex-, injury- and regimen-dependent differences in outcomes. Importantly the dose escalation regimen resulted in higher seeking behavior (post forced abstinence, context and cue driven nosepoking in the absence of fentanyl delivery), long lasting increased anxiety, immobility, and hyperactivity, as well as transient but full pain relief in SNI mice. Therefore, this regimen seems a better rodent model for translating outcomes to human chronic pain patients managed with opioids.