Dataset Information

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 Δ⁹-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 CB₁ 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 min 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 CB₂ antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB₁ receptor activation.

SUBMITTER: Nguyen JD

PROVIDER: S-EPMC7423642 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Nguyen Jacques D JD Creehan K M KM Grant Yanabel Y Vandewater Sophia A SA Kerr Tony M TM Taffe Michael A MA

Drug and alcohol dependence 20200716

The use of Δ9-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 ...[more]

PMID: 32717503

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Project description:Introduction: Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro. Materials and Methods: Potassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real time using FLIPR® membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 min. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels. Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%. Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.

Project description:CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.

Project description:BackgroundThere is an expanding unregulated market for a psychotropic compound called ∆8-Tetrahydrocannabinol (delta-8-THC) that is being derived from hemp, but a summary of adverse events related to delta-8-THC has not been publicly reported.MethodsThis case series assessed adverse events reported by delta-8-THC users on the Reddit forum r/Delta8 and compared these to delta-8-THC AEs in the US Food and Drug Administration Adverse Event Reporting System (FAERS). Delta-8-THC and cannabis AEs reported in FAERS were also compared. The r/Delta8 forum was selected because it includes a large sample of 98,700 registered individuals who publicly discuss their experiences using delta-8-THC. All r/Delta8 posts were obtained from August 20, 2020, through September 25, 2022. A random sample of r/Delta8 posts was drawn (n = 10,000) and filtered for posts in which delta-8-THC users reported an adverse event (n = 335). FAERS reports that listed delta-8-THC (N = 326) or cannabis (N = 7076) as a suspect product active ingredient were obtained. Adverse events claimed to result from delta-8-THC use were coded using Medical Dictionary for Regulatory Activities to system organ class and preferred term categories.ResultsThe absolute number of delta-8-THC adverse event reports (N = 2184, 95% CI = 1949-2426) and serious adverse event reports (N = 437; 95% CI = 339-541) on r/Delta 8 were higher than the adverse event reports (N = 326) and serious adverse event reports (N = 289) to FAERS. Psychiatric disorders were the most frequently cited system organ class in r/Delta8 adverse event reports, mentioned in 41.2% (95% CI = 35.8%-46.3%) of reports, followed by respiratory, thoracic and mediastinal disorders (29.3%, 95% CI = 25.1%-34.0%) and nervous system disorders (23.3%, 95% CI = 18.5%-27.5%). Anxiety (16.4%, 95% CI = 12.8-20.6), Cough (15.5%, 95% CI = 11.9-20.0) and Paranoia (9.3%, 95% CI = 6.3-12.5) were the most frequently cited preferred terms in adverse event reports. The overall prevalence of AEs reported for cannabis and delta-8-THC on FAERS were also similar when analyzed by system organ class (Pearson's r = 0.88).ConclusionsThe findings of this case series suggest that most of the adverse events reported by delta-8-THC users are like those reported during acute cannabis intoxication. This finding suggests that health care professionals follow similar treatment and management protocols, and that jurisdictions should clarify whether delta-8-THC can be sold as a hemp product.

Project description:Delta-9-tetrahydrocannabinol (Δ9-THC) is a naturally occurring psychoactive compound derived from the hemp plant Cannabis sativa. In 2015, EFSA established an acute reference dose (ARfD) of 1 μg/kg body weight (bw) for Δ9-THC and assessed acute dietary exposure from milk and dairy products. This resulted at the most 3% and 13% of the ARfD for adults and toddlers, respectively. Following the European Commission Recommendation 2016/2115 on the monitoring of the presence of Δ9-THC in food and the issuing of a new mandate, EFSA assessed the acute human exposure to Δ9-THC. 'Standard' food categories were used as proxies for consumption of hemp and hemp-based products. Twelve independent scenarios based on single food categories were considered and acute exposure was assessed for consumption days only for all age groups excluding infants. Occurrence data for Total-Δ9-THC (588 samples in total) were used for this assessment up to the highest reliable percentile for each food category. The EFSA ARfD of 1 μg/kg bw was exceeded in the adult high consumers of most considered hemp and hemp-containing products, under the lower-bound (LB) and upper-bound (UB) scenario. At the UB, acute exposure in adult high consumers was estimated based on the highest reliable percentile of occurrence, for Hemp seeds (P95, up to 9 μg/kg bw), Hemp oil (P95, up to 21 μg/kg bw), Tea (Infusion) (P95, up to 208 μg/kg bw), Breakfast cereals (P50, up to 1.3 μg/kg bw), Pasta (Raw) (P75, up to 6.4 μg/kg bw), Bread and rolls (P75, up to 1.3 μg/kg bw), Bread and rolls from hemp flour (P90, up to 4.1 μg/kg bw), Cereal bars (P50, up to 0.3 μg/kg bw), Fine bakery wares (P75, up to 5.1 μg/kg bw), Chocolate (Cocoa) products (P75, up to 1.1 μg/kg bw), Energy drinks (P75, up to 0.2 μg/kg bw), Dietary supplements (P75, up to 9.9 μg/kg bw), Beer and beer-like beverages (P90, up to 41 μg/kg bw). The use of proxies for the consumption of hemp and hemp-containing products, the limited number of occurrence data and the analytical limitations in the quantification of Δ9-THC represent the most important sources of uncertainty. Overall, exposure estimates presented in this report are expected to represent an overestimation of acute exposure to Δ9-THC in the EU.

Dataset Information

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

Publications

Explication of CB<sub>1</sub> receptor contributions to the hypothermic effects of Δ<sup>9</sup>-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats.

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