The long-term effects of repeated heroin vapor inhalation during adolescence on measures of nociception and anxiety-like behavior in adult Wistar rats

Abstract

Rationale Adolescents represent a vulnerable group due to increased experimentation with illicit substances that is often associated with the adolescent period, and because adolescent drug use can result in long-term effects that differ from those caused by drug use initiated during adulthood. Objectives The purpose of the present study was to determine the effects of repeated heroin vapor inhalation during adolescence on measures of nociception, and anxiety-like behavior during adulthood in female and male Wistar rats. Methods Rats were exposed twice daily to 30 min of heroin vapor from post-natal day (PND) 36 to PND 45. At 12 weeks of age, baseline thermal nociception was assessed across a range of temperatures with a warm-water tail-withdrawal assay. Anxiety-like behavior was assessed in an elevated plus-maze (EPM) and activity was measured in an open-field arena. Starting at 23 weeks of age, baseline thermal nociception was re-assessed, nociception was determined after acute heroin or naloxone injection, and anxiety-like behavior was redetermined in the EPM. Results Adolescent heroin inhalation altered baseline thermal nociception in female rats at 12 weeks of age and in both female and male rats at ~ 23 weeks. Heroin-treated animals exhibited anxiety-like behavior when tested in the elevated plus-maze, showed blunted heroin-induced analgesia, but exhibited no effect on naloxone-induced hyperalgesia. Conclusions The present study demonstrates that heroin vapor inhalation during adolescence produces behavioral and physiological consequences in rats that persist well into adulthood.

Persistent effects of repeated adolescent and adult heroin vapor inhalation in female Wistar rats

“…Importantly, the present study also shows that nociceptive effects of repeated opioids, which were confirmed out to ~16 weeks after the initial heroin vapor exposure in the Adolescent and Adult groups, are persistent. This is consistent with our previous work showing that repeated exposure to heroin vapor during adolescence increases baseline sensitivity to thermal stimuli and reduces the acute analgesic effects of subcutaneous heroin injections, in adulthood (Gutierrez et al 2022a). This study also extends prior results by showing that while the blunting of heroin-induced anti-nociception was present in both Adolescent-Exposed and Adult-Exposed groups, the hyperalgesic effects of the opioid antagonist naloxone were absent only in the Adolescent-Exposed group.…”

“…The reason for the discrepancies in prior findings is not clear, but potential causes include methodological differences, such as the stage of adolescence during which exposure occurred, dosing or testing procedures, or factors such as ambient lighting or the time of day when the behavioral testing was carried out. Our finding was particularly interesting given that we previously reported an increase in anxiety-like behavior following repeated adolescent exposure to heroin vapor (Gutierrez et al 2022a). Our studies were identical on several factors such as the dose, route of administration, age of treatment, strain of rat, etc., which limits the possible contributing factors.…”

“…Although all animals were adults by this point, to avoid confusion groups treated as adolescents shall be referred to as Adolescent-Exposed groups and those treated during adulthood as Adult-Exposed groups. A range of water temperatures (46 o C-52 o C) was used to assess baseline nociception, as previously described (Gutierrez et al 2022a). Tail-withdrawal tests were performed over two days, with one day in between test days.…”

“…Baseline nociception was again assessed in Adolescent and Adult groups at 17 weeks (PND 121) and 24 weeks (PND 170) of age, respectively. For this set of measurements, the target water temperature was 46 o C. This temperature was selected based on the findings from our initial baseline nociception experiment and our previous work (Gutierrez et al 2022a) showing that differences associated with repeated heroin vapor exposure are optimally detected at the lower range of temperatures.…”

“…We and others have reported success in using Electronic Nicotine Delivery Systems (ENDS), or more generally termed Electronic Drug Delivery Systems (EDDS), to deliver behaviorally active doses of opioids by inhalation in preclinical rodent models (Gutierrez et al 2021; Gutierrez et al 2022b; Gutierrez et al 2020; Marchette et al 2023; McConnell et al 2021; Moussawi et al 2020; Vendruscolo et al 2018). EDDS technology has also been used to probe the lasting effects of repeated adolescent vapor inhalation of drugs such as nicotine (Gutierrez et al 2024; Gutierrez et al 2023), THC (Gutierrez et al 2024; Nguyen et al 2020), and heroin (Gutierrez et al 2022a), and to determine lasting effects of in utero exposure to THC (Breit et al 2022; Breit et al 2020).…”