Effects of combined THC and heroin vapor inhalation in rats

Abstract

Rationale Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. Objectives To determine if heroin and Δ 9 -tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected. Methods Groups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50 mg/mL in propylene glycol vehicle; PG), THC (50 mg/mL), or the combination for assessment of effects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay. Results Heroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague–Dawley rats. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive effects on thermal nociception in both male and female Sprague–Dawley and Wistar rats. Conclusions This study shows that additive effects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

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

“…Recent studies also present compelling evidence for the inhalation self-administration of nicotine by rats (Lallai et al 2021;Smith et al 2020) and mice (Cooper et al 2021;Henderson and Cooper 2021). Inhalation of oxycodone, methadone, and heroin vapor produces anti-nociception (Gutierrez et al 2021(Gutierrez et al , 2022(Gutierrez et al , 2020Nguyen et al 2019), and heroin vapor inhalation elevates body temperature and produces biphasic effects on activity in rats (Gutierrez et al 2021). Self-administration of opioids by inhalation using EDDS technology has also recently been reported in rodents.…”

“…EDDS technology can be adapted to deliver active doses of many psychoactive drugs to rats by inhalation, including opioids. Non-contingent vapor delivery produces antinociception after inhalation of Δ9-tetrahydrocannabinol (THC) vapor (Gutierrez et al 2022;Javadi-Paydar et al 2018;Nguyen et al 2016b), decreases body temperature after nicotine, THC, or cannabidiol inhalation (Gutierrez et al 2022;Javadi-Paydar et al 2019a, 2019bNguyen et al 2016b), increases locomotor activity after exposure to nicotine (Javadi-Paydar et al 2019b), and methamphetamine (Nguyen et al 2016a(Nguyen et al , 2017, and decreases activity following THC (Gutierrez et al 2022). Additionally, EDDS delivery of nicotine vapor produces CPP in adult and adolescent rats (Frie et al 2020).…”

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

“…Rats were randomly assigned to the experimental (heroin inhalation) or control (propylene glycol inhalation) Adolescent Drug groups. Group sizes were determined based on prior work (Gutierrez et al 2021; Gutierrez et al 2022; Gutierrez et al 2020; Javadi-Paydar et al 2018; Nguyen et al 2018) Gutierrez et al, 2020; Gutierrez et al, 2021) and were designed to be equal. However, two male rats from Cohort 1 (C1) assigned to the repeated heroin group were lost during repeated vapor exposure presumably due to group huddling, immobility due to intoxication and perhaps respiratory suppression.…”

“…The bath was filled with water and the temperature was set and maintained at the target temperature (46 o C, 48 o C, 50 o C, or 52 o C depending on the experiment). Target temperatures were selected based on our previous work (Gutierrez et al 2021;Gutierrez et al 2022;Gutierrez et al 2020) and standard ranges of water temperatures for assessing nociception in rodents (Deuis et al 2017). The water bath was stirred, and the temperature was verified using a second thermometer prior to each rat assessment.…”

“…EDDS technology can be adapted to deliver active doses of many psychoactive drugs to rats by inhalation, including opioids. Non-contingent vapor delivery produces anti-nociception after inhalation of Δ9-tetrahydrocannabinol (THC) vapor (Gutierrez et al 2022; Javadi-Paydar et al 2018; Nguyen et al 2016b), decreases body temperature after nicotine, THC or cannabidiol inhalation (Gutierrez et al 2022; Javadi-Paydar et al 2019a; Javadi-Paydar et al 2019b; Javadi-Paydar et al 2018; Nguyen et al 2016b), increases locomotor activity after exposure to nicotine (Javadi-Paydar et al 2019b), and methamphetamine (Nguyen et al 2016a; Nguyen et al 2017), and decreases activity following THC (Gutierrez et al 2022). Additionally, EDDS delivery of nicotine vapor produces CPP in adult and adolescent rats (Frie et al 2020).…”