Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats

Abstract

The use of ∆ 9 -tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC.This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB 1 receptor, using pharmacological antagonist (SR141716, AM-251) approaches.Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 minutes after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB 2 antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB 1 receptor activation.

A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats

“…Rats had ad libitum access to food and water in their home cages and all experiments were performed in the rats' scotophase. Sample sizes were estimated based on results of prior studies investigating the effects of acute drug exposure on the telemetry endpoints (Aarde et al, 2017;Javadi-Paydar et al, 2018b;Nguyen et al, 2017;Nguyen et al, 2020a); group size was initially N=8 but two animals were initially lost due to surgical complications. All procedures were conducted under protocols approved by the Institutional Care and Use Committee of the University of California, San Diego.…”

Vapor exposure to Δ9-tetrahydrocannabinol (THC) slows locomotion of the Maine Lobster (Homarus americanus)

“…It required 60 minutes of exposure to THC to produce any significant effect (Figure 5B), which was very small in magnitude. Although THC has limited anti-nociceptive impact in rodents relative to an opioid (Nguyen et al, 2019) and has a limited dose-effect range due to this low ceiling, it is typically more robust in rodents than what was observed here.…”

“…It is thus of interest to develop assays to determine if lobsters exhibit thermal nociceptive behavioral responses and then to determine if those responses can be altered by THC exposure. The hot-water tail withdrawal assay in rats involves a reflexive tail movement when it is inserted in hot water (~48-52°C) and has been shown to be altered in rats after vapor inhalation of THC (Javadi-Paydar et al, 2018; Nguyen et al, 2016; Nguyen et al, 2020). Thus, one goal was to determine if a warm water immersion test of nociception is functional in the lobster and if so, if THC exposure decreased thermal nociception as it does in rodents (Tseng and Craft, 2001; Wiley et al, 2007).…”

THC modifies the impact of heroin delivered by vapor inhalation in rats

“…This is a novel observation since we did not include this in our prior study (Gutierrez et al, 2020a) which was the first to show efficacy of EDDS vapor delivery of heroin. While the effect of naloxone is perhaps expected, we’ve reported an unanticipated lack of effect of CB 1 antagonist/inverse agonist pre-treatment on THC vapor-induced hypothermia (Nguyen et al, 2020), so it was important to confirm opioid antagonist efficacy in this model. The failure to achieve a statistically reliable additive anti-nociceptive effect of heroin inhalation in the female group is likely due to a slightly more robust response to the heroin inhalation condition, compared with the males.…”

“…An opioid receptor antagonist study was included because we had not included this evidence in a prior study reporting heroin vapor effects on similar endpoints (Gutierrez et al, 2020a) and we’ve reported an unusual lack of effect of cannabinoid receptor 1 (CB 1 ) antagonist/inverse agonist pre-treatment on THC vapor-induced hypothermia (Nguyen et al, 2020). This latter was observed despite efficacy against the anti-nociceptive effects of inhaled THC and the thermoregulatory effects in injected THC thus it was of interest to determine if a nonselective opioid receptor antagonist was effective against effects of inhaled heroin on temperature, activity and anti-nociceptive responses.…”