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.

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.

The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

2021 ◽  
Vol 20 ◽  
Author(s):  
Aboagyewaah Oppong-Damoah ◽  
Brenda Marie Gannon ◽  
Kevin Sean Murnane
Keyword(s):  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Health Concern ◽  
Cb2 Receptor ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Clinical Phase ◽  
Anti Inflammatory ◽  
Cb1 Antagonists ◽  
Psychiatric Side Effects

: Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD. However, CB1 agonists have not been investigated for the treatment of AUD because they stimulate the motivational properties of alcohol, increase alcohol intake, and have the tendency to be abused. Preclinical data suggest significant potential for the use of CB1 antagonists to treat AUD; however, a clinical phase I/II trial with SR14716A (rimonabant), a CB1 receptor antagonist/inverse agonist showed that it produced serious neuropsychiatric adverse events such as anxiety, depression, and even suicidal ideation. This has redirected the field to focus on alternative components of the endocannabinoid system, including cannabinoid type 2 (CB2) receptor agonists as a potential therapeutic target for AUD. CB2 receptor agonists are of particular interest because they can modulate the reward pathway, reduce abuse-related effects of alcohol, reverse neuroinflammation, improve cognition, and exhibit anti-inflammatory and neuroprotective effects, without exhibiting the psychiatric side effects seen with CB1 antagonists. Accordingly, this article presents an overview of the studies reported in the literature that have investigated CB2 receptor agonists with regards to AUD and provides commentary as to whether this receptor is a worthy target for continued investigation.

scholarly journals Implication of the Endocannabinoid System in the Locomotor Hyperactivity Associated with Congenital Hypothyroidism

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2657-2666 ◽  
Author(s):  
Teresa Asúa ◽  
Ainhoa Bilbao ◽  
Miguel Angel Gorriti ◽  
Jose Antonio Lopez-Moreno ◽  
Maria del Mar Álvarez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Cannabinoid Receptor ◽  
Receptor Gene ◽  
Hormone Replacement ◽  
Adult Life ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Hormone Deficiency ◽  
Receptor Gene Expression

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB1) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB1 receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB1 receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

scholarly journals Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping

2020 ◽  
Vol 21 (17) ◽  
pp. 6252 ◽  
Author(s):  
Francesco Rusconi ◽  
Tiziana Rubino ◽  
Elena Battaglioli
Keyword(s):  
Stress Responses ◽  
Glutamate Release ◽  
Disease Onset ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Protective Role ◽  
Cb1 Receptor ◽  
Traumatic Experiences ◽  
Stress Coping ◽  
As Stress

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety. A relevant homeostatic pathway is the endocannabinoid system (ECS). In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism. As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization. In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1. We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.

scholarly journals Type 2 Diabetes Alters Vascular Cannabinoid Receptor 1 Expression, Phosphorylation Status, and Vasorelaxation in Rat Aorta

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4948
Author(s):  
Enrique Sánchez-Pastor ◽  
Xóchitl Trujillo ◽  
Christian Ramos-Flores ◽  
Mónica Ríos-Silva ◽  
Felipa Andrade ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Rat Aorta ◽  
Cardiovascular Complications ◽  
Cb1 Receptor ◽  
Receptor Expression ◽  
Vasorelaxant Effect

Previous studies have suggested a role of the endocannabinoid system in metabolic diseases, such as diabetes. We investigated the effect of diabetes on cannabinoid receptor type 1 (CB1) expression and cannabinoid-induced vasorelaxation in rat aorta rings. Aortas from healthy rats and from rats with experimentally induced diabetes were used to compare the vasorelaxant effect of the cannabinoid agonist arachidonylcyclopropylamide (ACPA) and CB1 expression and localization. After 4–8 weeks of diabetes induction, CB1 receptor expression and CB1 phosphorylation were higher in aortic rings, in association with greater vasorelaxation induced by the CB1 agonist ACPA compared to healthy rats. The vasorelaxant effect observed in healthy rats is similar throughout the study. Further studies are needed to elucidate the implications of CB1 receptor overexpression in diabetes and its influence on the progression of the cardiovascular complications of this metabolic disease.

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.

scholarly journals Endocannabinoids and Their Receptors as Targets for Obesity Therapy

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2531-2536 ◽  
Author(s):  
Annette D. de Kloet ◽  
Stephen C. Woods
Keyword(s):  
Energy Homeostasis ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Metabolic Effects ◽  
Peripheral Tissues ◽  
Anabolic Action ◽  
Obesity Therapy ◽  
Glucose Profiles ◽  
Cb1 Antagonists

As the incidence of obesity continues to increase, the development of effective therapies is a high priority. The endocannabinoid system has emerged as an important influence on the regulation of energy homeostasis. The endocannabinoids anandamide and 2-arachidonoylglycerol act on cannabinoid receptor-1 (CB1) in the brain and many peripheral tissues causing a net anabolic action. This includes increasing food intake, and causing increased lipogenesis and fat storage in adipose tissue and liver. The endocannabinoid system is hyperactive in obese humans and animals, and treating them with CB1 antagonists causes weight loss and improved lipid and glucose profiles. Although clinical trials with CB1 antagonists have yielded beneficial metabolic effects, concerns about negative affect have limited the therapeutic potential of the first class of CB1 antagonists available.

Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood

2005 ◽  
Vol 230 (4) ◽  
pp. 225-234 ◽  
Author(s):  
Ester Fride ◽  
Tatyana Bregman ◽  
Tim C. Kirkham
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Critical Role ◽  
Growth Failure ◽  
Endocannabinoid System ◽  
Failure To Thrive ◽  
Receptor Activation ◽  
Organ Systems

The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB, receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB, receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB, receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause.

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.

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