Contribution of Hypothermia and CB1 Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model

The plant cannabinoid Δ9-tetrahydrocannabinol and the endocannabinoid anandamide increase the amount of sleep via a CB1 receptor mediated mechanism. Here, we explored the use of a novel electroencephalogram (EEG) recording device based on wireless EEG microchip technology (Neurologger) in freely-moving rats, and its utility in experiments of cannabinoids-induced alterations of EEG/vigilance stages. EEG was recorded through epidural electrodes placed above pre-frontal and parietal cortex (overlaying the dorsal hippocampus). As cannabinoids, we acutely administered the full synthetic CB1 receptor agonist, WIN55,212-2 (1 mg/kg), and the antagonist/inverse agonist, AM251 (2 mg/kg), either alone or together through the intraperitoneal route. WIN55,212-2 increased the total amount of NREM sleep and the length of each NREM bout, but this was unlikely due to CB1 receptor activation since it was not prevented by AM251. However, WIN55,212-2 also lowered overall EEG spectral power especially in theta and alpha frequency bands during wakefulness and NREM sleep, and this effect was reversed by AM251. The antagonist/inverse agonist caused no sleep alterations by itself and moderately increased spectral power in Theta, alpha and beta frequency bands during NREM sleep when administered on its own. Implications of endocannabinoid modulation of the sleep-wake cycle and its possible interactions with other transmitter systems are considered.

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Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00354.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. L267-L277 ◽

Cited By ~ 10

Author(s):

Z. Helyes ◽

Á. Kemény ◽

K. Csekő ◽

É. Szőke ◽

K. Elekes ◽

...

Keyword(s):

Tobacco Smoke ◽

Airway Hyperresponsiveness ◽

Inflammatory Cell ◽

Cannabinoid Receptor ◽

Receptor Activation ◽

Cb1 Receptor ◽

Whole Body ◽

Myeloperoxidase Activity ◽

Tissue Destruction ◽

Cell Hyperplasia

Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor.

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U-46619 but not serotonin increases endocannabinoid content in middle cerebral artery: evidence for functional relevance

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00978.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. H2694-H2701 ◽

Cited By ~ 18

Author(s):

David J. Rademacher ◽

Sachin Patel ◽

W.-S. Vanessa Ho ◽

Amanda M. Savoie ◽

Nancy J. Rusch ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Receptor Agonist ◽

Cannabinoid Receptor ◽

Cerebral Arteries ◽

Receptor Activation ◽

Maximal Effect ◽

Receptor Antagonists ◽

Local Formation ◽

Sr 141716

Cerebral vascular smooth muscle cells express the CB1 cannabinoid receptor, and CB1 receptor agonists produce vasodilation of cerebral arteries. The purpose of this study was to determine whether vasoconstriction of rat middle cerebral artery (MCA) results in the local formation of endocannabinoids (eCBs), which, via activation of CB1 receptors, oppose the vasoconstriction in a feedback manner. The thromboxane A2 (TXA2) mimetic U-46619 significantly increased N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) content of isolated MCA, whereas 5-hydroxytrypamine (5-HT) decreased AEA and 2-AG content. If eCBs play a feedback role in the regulation of MCA tone, then CB1 receptor antagonists should enhance the constriction of MCA produced by U-46619 but not 5-HT. U-46619 caused concentration-dependent constrictions of endothelium-denuded MCA. Two CB1 receptor antagonists SR-141716 and AM-251 decreased the EC50 value for U-46619 to constrict endothelium-denuded MCA without affecting the maximal effect. A low concentration of CB1 receptor agonist Win-55212-2 (30 nM) produced vasodilation of MCAs constricted with low but not saturating concentrations of U-46619. SR-141716 had no effect on the 5-HT concentration-contraction relationship. These data suggest that TXA2 receptor activation increases MCA eCB content, which, via activation of CB1 receptors, reduces the constriction produced by moderate concentrations of the TXA2 agonist. Although 5-HT-induced vasoconstriction is reduced by exogenous CB1 receptor agonist, activation of 5-HT receptors does not increase eCB content. These results suggest that MCA production of eCBs is not regulated by constriction per se but likely via a signaling pathway that is specific for TXA2 receptors and not 5-HT receptors.

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Cannabinoid and Kappa Opioid Receptors Reduce Potassium K Current via Activation of Gs Proteins in Cultured Hippocampal Neurons

Journal of Neurophysiology ◽

10.1152/jn.2000.84.5.2356 ◽

2000 ◽

Vol 84 (5) ◽

pp. 2356-2364 ◽

Cited By ~ 63

Author(s):

Robert E. Hampson ◽

Jian Mu ◽

Sam A. Deadwyler

Keyword(s):

Protein Kinase ◽

Receptor Antagonist ◽

Hippocampal Neurons ◽

Receptor Agonist ◽

Cannabinoid Receptor ◽

Cb1 Receptor ◽

Kappa Opioid ◽

K Current ◽

Kappa Receptor ◽

Cultured Hippocampal Neurons

The current study showed that potassium K current ( I K), which is evoked at depolarizing potentials between −30 and +40 mV in cultured hippocampal neurons, was significantly reduced by exposure to the CB1 cannabinoid receptor agonist WIN 55,212-2 (WIN-2). WIN-2 (20–40 nM) produced an average 45% decrease in I K amplitude across all voltage steps, which was prevented by SR141716A, the CB1 receptor antagonist. The cannabinoid receptor has previously been shown to be Gi/o protein-linked to several cellular processes; however, the decrease in I Kwas unaffected by modulators of Gi/o proteins and agents that alter levels of protein kinase A. In contrast, CB1 receptor-mediated or direct activation of Gsproteins with cholera toxin (CTX) produced the same decrease in I K amplitude as WIN-2, and the latter was blocked in CTX-treated cells. Gs protein inhibition via GDPβS also eliminated the effects of WIN-2 on I K. Consistent with this outcome, activation of protein kinase C (PKC) by arachidonic acid produced similar effects to WIN-2 and CTX. Kappa opioid receptor agonists, which also reduce I K amplitude via Gs proteins, were compared with WIN-2 actions on I K. The kappa receptor agonist U50,488 reduced I K amplitude in the same manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased I K amplitude and significantly reduced the effect of co-administered WIN-2. The results indicate that CB1 and kappa receptor activation is additive with respect to I K amplitude, suggesting that CB1 and kappa receptors share a common Gs protein signaling pathway involving PKC.

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Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors

Anesthesiology ◽

10.1097/00000542-200310000-00031 ◽

2003 ◽

Vol 99 (4) ◽

pp. 955-960 ◽

Cited By ~ 171

Author(s):

Aline Quartilho ◽

Heriberto P. Mata ◽

Mohab M. Ibrahim ◽

Todd W. Vanderah ◽

Frank Porreca ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Thermal Hyperalgesia ◽

Receptor Activation ◽

Cb1 Receptor ◽

Cb2 Receptor ◽

Inflammatory Hyperalgesia ◽

Selective Antagonist ◽

Receptor Agonists ◽

Cb2 Receptors ◽

Cns Effects

Background Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia. Methods Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251. Results AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection. Conclusions Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.

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CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽

10.3390/molecules26175413 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5413

Author(s):

Luciana M. Leo ◽

Mary E. Abood

Keyword(s):

Adverse Effects ◽

G Protein ◽

Conformational Changes ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Receptor Activation ◽

Cb1 Receptor ◽

Cb1 Cannabinoid Receptor ◽

Biased Signaling ◽

G Protein Coupled

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.

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A cannabinoid receptor agonist shows anti-inflammatory and survival properties in human SARS-CoV-2-infected iPSC-derived cardiomyocytes

10.1101/2021.02.20.431855 ◽

2021 ◽

Author(s):

Luiz Guilherme H. S. Aragão ◽

Júlia T. Oliveira ◽

Jairo R. Temerozo ◽

Mayara A. Mendes ◽

José Alexandre Salerno ◽

...

Keyword(s):

Receptor Agonist ◽

Cannabinoid Receptor ◽

List Type ◽

Protective Effects ◽

Cardiac Damage ◽

Necrosis Factor Alpha ◽

Risk Of Mortality ◽

Factor Alpha ◽

Anti Inflammatory ◽

Human Ipsc

AbstractCoronavirus disease 2019 (COVID-19) is caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect several organs and lead to loss of vital organ function, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 is myocardial injury, caused both directly and indirectly by SARS-CoV-2, and which is associated with a high risk of mortality. One of the hallmarks of severe COVID-19 is the “cytokine storm”, at which point the immune system malfunctions, leading to possible organ failure and death. Cannabinoids are known to have anti-inflammatory properties by negatively modulating the release of pro-inflammatory cytokines. Herein, we investigated the effects of the cannabinoid agonist WIN 55,212-2 (WIN) on SARS-CoV-2-infected human iPSC-derived cardiomyocytes (hiPSC-CMs). Although WIN did not modulate angiotensin-converting enzyme II, nor reduced SARS-CoV-2 infection and replication in hiPSC-CMs at the conditions tested, it had anti-inflammatory and protective effects by reducing the levels of interleukins 6, 8,18 and tumor necrosis factor-alpha (TNF-α) and lactate dehydrogenase (LDH) activity in these cells without causing hypertrophic cardiac damage. These findings suggest that cannabinoids should be further investigated as an alternative therapeutic tool for the treatment of COVID-19.HighlightsHuman iPSC-derived cardiomyocytes (hiPSC-CMs) express CB1 receptor.The cannabinoid receptor agonist, WIN 55,212-2 (WIN), does not influence SARS-CoV-2 infection in hiPSC-CMs.WIN reduces inflammation and death in SARS-CoV-2-infected hiPSC-CMs.

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