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

2017 ◽  
Vol 313 (2) ◽  
pp. L267-L277 ◽  
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.

Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors

2003 ◽  
Vol 99 (4) ◽  
pp. 955-960 ◽  
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.

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

2013 ◽  
Vol 304 (2) ◽  
pp. G181-G192 ◽  
Author(s):  
Thomas Michler ◽  
Martin Storr ◽  
Johannes Kramer ◽  
Stefanie Ochs ◽  
Antje Malo ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Western Blotting ◽  
Map Kinases ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Pancreatic Acini

The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB1) and 2 (CB2). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH2-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB1−/−, and MK2−/− mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB1 and CB2 are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB2 on apoptotic cells occurred. The unselective CB1/CB2 agonist HU210 ameliorated pancreatitis in wild-type and CB1−/− mice, indicating that this effect is mediated by CB2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved pathology. Stimulation with a selective CB2 agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2−/− mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2−/− mouse model we reveal a novel CB2-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.

scholarly journals CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽  
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.

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

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40889 ◽  
Author(s):  
Noriko Suzuki ◽  
Motohisa Suzuki ◽  
Kazuhiro Hamajo ◽  
Koji Murakami ◽  
Tetsuya Tsukamoto ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Protective Effects

scholarly journals CB2 Receptor Activation Ameliorates the Proinflammatory Activity in Acute Lung Injury Induced by Paraquat

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Zhenning Liu ◽  
Yu Wang ◽  
Hongyu Zhao ◽  
Qiang Zheng ◽  
Li Xiao ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cannabinoid Receptor ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Receptor Activation ◽  
Lung Edema ◽  
Myeloperoxidase Activity ◽  
Cb2 Receptor ◽  
Arterial Blood ◽  
Proinflammatory Activity

Paraquat, a widely used herbicide, is well known to exhibit oxidative stress and lung injury. In the present study, we investigated the possible underlying mechanisms of cannabinoid receptor-2 (CB2) activation to ameliorate the proinflammatory activity induced by PQ in rats. JWH133, a CB2 agonist, was administered by intraperitoneal injection 1 h prior to PQ exposure. After PQ exposure for 4, 8, 24, and 72 h, the bronchoalveolar lavage fluid was collected to determine levels of TNF-αand IL-1β, and the arterial blood samples were collected for detection of PaO2level. At 72 h after PQ exposure, lung tissues were collected to determine the lung wet-to-dry weight ratios, myeloperoxidase activity, lung histopathology, the protein expression level of CB2, MAPKs (ERK1/2, p38MAPK, and JNK1/2), and NF-κBp65. After rats were pretreated with JWH133, PQ-induced lung edema and lung histopathological changes were significantly attenuated. PQ-induced TNF-αand IL-1βsecretion in BALF, increases of PaO2in arterial blood, and MPO levels in the lung tissue were significantly reduced. JWH133 could efficiently activate CB2, while inhibiting MAPKs and NF-κB activation. The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI, and it potentially contributed to the suppression of the activation of MAPKs and NF-κB pathways.

scholarly journals Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Magali Boucher ◽  
Cyndi Henry ◽  
Alexis Dufour-Mailhot ◽  
Fatemeh Khadangi ◽  
Ynuk Bossé
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Airway Hyperresponsiveness ◽  
Inflammatory Cell ◽  
Allergic Inflammation ◽  
Cell Hyperplasia ◽  
Once Daily ◽  
Dust Mite ◽  
Pulmonary Allergic Inflammation

The contractility of airway smooth muscle (ASM) is labile. Although this feature can greatly modulate the degree of airway responsiveness in vivo, the extent by which ASM’s contractility is affected by pulmonary allergic inflammation has never been compared between strains of mice exhibiting a different susceptibility to develop airway hyperresponsiveness (AHR). Herein, female C57BL/6 and BALB/c mice were treated intranasally with either saline or house dust mite (HDM) once daily for 10 consecutive days to induce pulmonary allergic inflammation. The doses of HDM were twice greater in the less susceptible C57BL/6 strain. All outcomes, including ASM contractility, were measured 24 h after the last HDM exposure. As expected, while BALB/c mice exposed to HDM became hyperresponsive to a nebulized challenge with methacholine in vivo, C57BL/6 mice remained normoresponsive. The lack of AHR in C57BL/6 mice occurred despite exhibiting more than twice as much inflammation than BALB/c mice in bronchoalveolar lavages, as well as similar degrees of inflammatory cell infiltrates within the lung tissue, goblet cell hyperplasia and thickening of the epithelium. There was no enlargement of ASM caused by HDM exposure in either strain. Unexpectedly, however, excised tracheas derived from C57BL/6 mice exposed to HDM demonstrated a decreased contractility in response to both methacholine and potassium chloride, while tracheas from BALB/c mice remained normocontractile following HDM exposure. These results suggest that the lack of AHR in C57BL/6 mice, at least in an acute model of HDM-induced pulmonary allergic inflammation, is due to an acquired ASM hypocontractility.

Cannabinoid Receptor Modulation of Synapses Received by Cerebellar Purkinje Cells

2000 ◽  
Vol 83 (3) ◽  
pp. 1167-1180 ◽  
Author(s):  
Kanji A. Takahashi ◽  
David J. Linden
Keyword(s):  
Neurotransmitter Release ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Vesicle Release ◽  
Voltage Gated ◽  
Postsynaptic Currents ◽  
Voltage Gated Channels ◽  
Release Processes

The high density of cannabinoid receptors in the cerebellum and the degradation of motor coordination produced by cannabinoid intoxication suggest that synaptic transmission in the cerebellum may be strongly regulated by cannabinoid receptors. Therefore the effects of exogenous cannabinoids on synapses received by Purkinje cells were investigated in rat cerebellar slices. Parallel fiber–evoked (PF) excitatory postsynaptic currents (EPSCs) were strongly inhibited by bath application of the cannabinoid receptor agonist WIN 55212-2 (5 μM, 12% of baseline EPSC amplitude). This effect was completely blocked by the cannabinoid CB1 receptor antagonist SR 141716. It is unlikely that this was the result of alterations in axonal excitability because fiber volley velocity and kinetics were unchanged and a cannabinoid-induced decrease in fiber volley amplitude was very minor (93% of baseline). WIN 55212-2 had no effect on the amplitude or frequency of spontaneously occurring miniature EPSCs (mEPSCs), suggesting that the effect of CB1 receptor activation on PF EPSCs was presynaptically expressed, but giving no evidence for modulation of release processes after Ca2+influx. EPSCs evoked by climbing fiber (CF) stimulation were less powerfully attenuated by WIN 55212-2 (5 μM, 74% of baseline). Large, action potential–dependent, spontaneously occurring inhibitory postsynaptic currents (sIPSCs) were either severely reduced in amplitude (<25% of baseline) or eliminated. Miniature IPSCs (mIPSCs) were reduced in frequency (52% of baseline) but not in amplitude, demonstrating suppression of presynaptic vesicle release processes after Ca2+ influx and suggesting an absence of postsynaptic modulation. The decrease in mIPSC frequency was not large enough to account for the decrease in sIPSC amplitude, suggesting that presynaptic voltage-gated channel modulation was also involved. Thus, while CB1 receptor activation reduced neurotransmitter release at all major classes of Purkinje cell synapses, this was not accomplished by a single molecular mechanism. At excitatory synapses, cannabinoid suppression of neurotransmitter release was mediated by modulation of voltage-gated channels in the presynaptic axon terminal. At inhibitory synapses, in addition to modulation of presynaptic voltage-gated channels, suppression of the downstream vesicle release machinery also played a large role.

scholarly journals The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6178
Author(s):  
Saoirse Elizabeth O’Sullivan ◽  
Andrew S. Yates ◽  
Richard K. Porter
Keyword(s):  
Body Weight ◽  
Cannabinoid Receptor ◽  
Clinical Stage ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Obesity And Diabetes ◽  
Satiety Hormone ◽  
Cb1 Antagonists ◽  
Therapeutic Utility

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut–brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.

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