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1.
J Pharmacol Exp Ther ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858091

RESUMO

Δ9-tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), that may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via i.p injection, tail vein i.v injection, or oral gavage (p.o), and whole blood compound levels were measured to determine pharmacokinetic parameters (Cmax, Tmax, t1/2, AUC, Vd, ClS, k and F) while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved Tmax at 30 min for all routes of administration. The maximum concentration at 30 min was not different between i.v. and i.p. routes, but the p.o. Cmax was significantly lower. THC had a 10 min time to the maximum concentration - which was the first blood collection time point - for i.v. and i.p., and 60 min for p.o. with a lower Cmax for i.p. and p o. compared to i.v When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception, and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for PK differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. Significance Statement In this study we establish that the primary metabolite of THC - 11-OH-THC - displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

2.
Eur J Neurosci ; 55(4): 1063-1078, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33370468

RESUMO

There is significant interest in the use of cannabinoids for the treatment of many epilepsies including absence epilepsy (AE). Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of AE including the presence of spike-and-wave discharges (SWDs) on electroencephalogram (EEG) and behavioral comorbidities, such as elevated anxiety. However, the effects of cannabis plant-based phytocannabinoids have not been tested in GAERS. Therefore, we investigated how SWDs in GAERS are altered by the two most common phytocannabinoids, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), and exposure to smoke from two different chemovars of cannabis. Animals were implanted with bipolar electrodes in the somatosensory cortex and EEGs were recorded for 2 hr. Injected THC (1-10 mg/kg, i.p.) dose-dependently increased SWDs to over 200% of baseline. In contrast, CBD (30-100 mg/kg, i.p.) produced a ~50% reduction in SWDs. Exposure to smoke from a commercially available chemovar of high-THC cannabis (Mohawk, Aphria Inc.) increased SWDs whereas a low-THC/high-CBD chemovar of cannabis (Treasure Island, Aphria Inc.) did not significantly affect SWDs in GAERS. Pre-treatment with a CB1R antagonist (SR141716A) did not prevent the high-THC cannabis smoke from increasing SWDs, suggesting that the THC-mediated increase may not be CB1R-dependent. Plasma concentrations of THC and CBD were similar to previously reported values following injection and smoke exposure. Compared to injected CBD, it appears Treasure Island did not increase plasma levels sufficiently to observe an anti-epileptic effect. Together these experiments provide initial evidence that acute phytocannabinoid administration exerts the biphasic modulation of SWDs and may differentially impact patients with AE.


Assuntos
Canabidiol , Canabinoides , Cannabis , Epilepsia Tipo Ausência , Animais , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides , Canabinoides/farmacologia , Dronabinol , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Humanos , Ratos , Ratos Wistar
3.
Neurobiol Learn Mem ; 192: 107624, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35513236

RESUMO

Executive functions including working memory (WM) and attention are altered following Cannabis exposure in humans. To test for similar effects in a rodent model, we exposed adult male rats to acute Cannabis smoke before testing them on touchscreen-based tasks that assess these executive processes. The trial-unique, delayed nonmatching-to-location (TUNL) task was used to evaluate WM, task performance at different spatial pattern separations, and response latencies. The five-choice serial reaction time task (5-CSRTT) was used to measure attention, impulsivity, perseveration, and response latencies. Rats were exposed acutely to high- Δ9-tetrahydrocannabinol (THC), low-CBD (Mohawk) and low-THC, high-CBD (Treasure Island) strains of Cannabis smoke using a chamber inhalation system. The effects of Cannabis smoke were directly compared to systemic Δ9-THC injection (3.0 mg/kg; i.p.). TUNL task performance was significantly impaired following acute high-THC smoke exposure or THC injections, but not low-THC smoke exposure, with no effects on response latencies. Fewer total trials and selection trials were also performed following THC injections. Performance was poorer for smaller separation distances in all groups. Neither acute smoke exposure, nor injected THC, impacted attentional processes, impulsivity, perseverations, or response latencies in the 5-CSRTT. Pharmacokinetic analysis of rat plasma revealed significantly higher THC levels following injections than smoke exposure 30 min following treatment. Exposure to low-THC, high-CBD Cannabis smoke significantly increased CBD in plasma, relative to the other treatments. Taken together, our results suggest that WM processes as measured by the TUNL task are more sensitive to THC exposure than the attentional and impulsivity measures assessed using the 5-CSRTT.


Assuntos
Canabidiol , Cannabis , Animais , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Masculino , Memória de Curto Prazo , Ratos , Ratos Long-Evans , Tempo de Reação , Fumaça
4.
Brain Sci ; 13(2)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36831860

RESUMO

The endocannabinoid and orexin systems share many biological functions, including wakefulness, stress response, reward processing, and mood. While these systems work against one another with respect to arousal, chronic stress-induced downregulation of both systems often leads to anhedonia or the inability to experience pleasure from natural rewards. In the current study, a 24 h restraint stress test (24 h RST) reduced sucrose preference in adult male and female C57BL/6 mice. Prior to the stressor, subsets of mice were intraperitoneally administered cannabinoid and orexin receptor agonists, antagonists, and combinations of these drugs. Restraint mice that received the cannabinoid receptor type 1 (CB1R) antagonist SR141716A, orexin receptor type 2 (OX2R) agonist YNT-185, and the combination of SR141716A and YNT-185, exhibited less anhedonia compared to vehicle/control mice. Thus, the 24 h RST likely decreased orexin signaling, which was then restored by YNT-185. Receptor colocalization analysis throughout mesocorticolimbic brain regions revealed increased CB1R-OX1R colocalization from SR141716A and YNT-185 treatments. Although a previous study from our group showed additive cataleptic effects between CP55,940 and the dual orexin receptor antagonist (TCS-1102), the opposite combination of pharmacological agents proved additive for sucrose preference. Taken together, these results reveal more of the complex interactions between the endocannabinoid and orexin systems.

5.
Prog Mol Biol Transl Sci ; 195: 27-45, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36707154

RESUMO

Neurological crosstalk between the endocannabinoid and estrogen systems has been a growing topic of discussion over the last decade. Although the main estrogenic ligand, estradiol (E2), influences endocannabinoid signaling in both male and female animals, the latter experiences significant and rhythmic fluctuations in E2 as well as other sex hormones. This is referred to as the menstrual cycle in women and the estrus cycle in rodents such as mice and rats. Consisting of 4 distinct hormone-driven phases, the rodent estrus cycle modulates both endocannabinoid and exogenous cannabinoid signaling resulting in unique behavioral outcomes based on the cycle phase. For example, cannabinoid receptor agonist-induced antinociception is greatest during proestrus and estrus, when circulating and brain levels of E2 are high, as compared to metestrus and diestrus when E2 concentrations are low. Pain processing occurs throughout the cerebral cortex and amygdala of the forebrain; periaqueductal grey of the midbrain; and medulla and spine of the hindbrain. As a result, past molecular investigations on these endocannabinoid-estrogen system interactions have focused on these specific brain regions. Here, we will bridge regional molecular trends with neurophysiological evidence of how plasma membrane estrogen receptor (ER) activation by E2 leads to postsynaptic endocannabinoid synthesis, retrograde signaling, and alterations in inhibitory neurotransmission. These signaling pathways depend on ER heterodimers, current knowledge of which will also be detailed in this review. Overall, the aim of this review article is to systematically summarize how the cannabinoid receptors and endocannabinoids change in expression and function in specific brain regions throughout the estrus cycle.


Assuntos
Endocanabinoides , Estradiol , Ratos , Feminino , Masculino , Camundongos , Animais , Estradiol/farmacologia , Estradiol/metabolismo , Endocanabinoides/metabolismo , Roedores , Estro/fisiologia , Estrogênios/metabolismo , Encéfalo/metabolismo
6.
Sci Rep ; 13(1): 21070, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-38030657

RESUMO

Cannabis sativa has gained popularity as a "natural substance", leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague-Dawley rats were treated daily from gestational day 6-20 with either room air, i.p. vehicle, inhaled high-Δ9-tetrahydrocannabinol (THC) (18% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.7% THC, 13% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.


Assuntos
Canabidiol , Canabinoides , Cannabis , Alucinógenos , Humanos , Feminino , Ratos , Gravidez , Animais , Canabinoides/análise , Cannabis/efeitos adversos , Cannabis/metabolismo , Citocinas , Fumaça/efeitos adversos , Saúde Materna , Ratos Sprague-Dawley , Placenta/metabolismo , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides , Quimiocinas , Dronabinol
7.
Front Pharmacol ; 13: 956030, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091813

RESUMO

Cannabis sativa contains more than 120 cannabinoids and 400 terpene compounds (i.e., phytomolecules) present in varying amounts. Cannabis is increasingly available for legal medicinal and non-medicinal use globally, and with increased access comes the need for a more comprehensive understanding of the pharmacology of phytomolecules. The main transducer of the intoxicating effects of Cannabis is the type 1 cannabinoid receptor (CB1R). ∆9-tetrahydrocannabinolic acid (∆9-THCa) is often the most abundant cannabinoid present in many cultivars of Cannabis. Decarboxylation converts ∆9-THCa to ∆9-THC, which is a CB1R partial agonist. Understanding the complex interplay of phytomolecules-often referred to as "the entourage effect"-has become a recent and major line of inquiry in cannabinoid research. Additionally, this interest is extending to other non-Cannabis phytomolecules, as the diversity of available Cannabis products grows. Here, we chose to focus on whether 10 phytomolecules (∆8-THC, ∆6a,10a-THC, 11-OH-∆9-THC, cannabinol, curcumin, epigallocatechin gallate, olivetol, palmitoylethanolamide, piperine, and quercetin) alter CB1R-dependent signaling with or without a co-treatment of ∆9-THC. Phytomolecules were screened for their binding to CB1R, inhibition of forskolin-stimulated cAMP accumulation, and ßarrestin2 recruitment in Chinese hamster ovary cells stably expressing human CB1R. Select compounds were assessed further for cataleptic, hypothermic, and anti-nociceptive effects on male mice. Our data revealed partial agonist activity for the cannabinoids tested, as well as modulation of ∆9-THC-dependent binding and signaling properties of phytomolecules in vitro and in vivo. These data represent a first step in understanding the complex pharmacology of Cannabis- and non-Cannabis-derived phytomolecules at CB1R and determining whether these interactions may affect the physiological outcomes, adverse effects, and abuse liabilities associated with the use of these compounds.

8.
Pharmacol Res Perspect ; 10(3): e00950, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35466560

RESUMO

Sexual dimorphisms are observed in cannabinoid pharmacology. It is widely reported that female animals are more sensitive to the cataleptic, hypothermic, antinociceptive, and anti-locomotive effects of cannabinoid receptor agonists such as CP55,940. Despite awareness of these sex differences, there is little consideration for the pharmacodynamic differences within females. The mouse estrus cycle spans 4-5 days and consists of four sex hormone-mediated phases: proestrus, estrus, metestrus, and diestrus. The endocannabinoid system interacts with female sex hormones including ß-estradiol, which may influence receptor expression throughout the estrus cycle. In the current study, sexually mature female C57BL/6 mice in either proestrus or metestrus were administered either 1 mg/kg i.p. of the cannabinoid receptor agonist CP55,940 or vehicle. Mice then underwent the tetrad battery of behavioral assays measuring catalepsy, internal body temperature, thermal nociception, and locomotion. Compared with female mice in metestrus, those in proestrus were more sensitive to the anti-nociceptive effects of CP55,940. A similar trend was observed in CP55,940-induced catalepsy; however, this difference was not significant. As for cannabinoid receptor expression in brain regions underlying antinociception, the spine tissue of proestrus mice that received CP55,940 exhibited increased expression of cannabinoid receptor type 1 relative to treatment-matched mice in metestrus. These results affirm the importance of testing cannabinoid effects in the context of the female estrus cycle.


Assuntos
Agonistas de Receptores de Canabinoides , Canabinoides , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Estro , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Canabinoides
9.
Front Pharmacol ; 13: 919605, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386195

RESUMO

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington's disease.

10.
Front Neurosci ; 15: 790546, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34992518

RESUMO

The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

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