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1.
Sci Rep ; 11(1): 8232, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33859287

ABSTRACT

Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an "entourage effect" whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and ß-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.


Subject(s)
Cannabinoid Receptor Agonists/pharmacology , Cannabinoids/pharmacology , Cannabis , Terpenes/pharmacology , Animals , Behavior, Animal/drug effects , Benzoxazines/pharmacology , CHO Cells , Cannabinoid Receptor Agonists/isolation & purification , Cannabis/chemistry , Catalepsy/chemically induced , Catalepsy/pathology , Cricetulus , Drug Synergism , Female , Locomotion/drug effects , Male , Mice , Mice, Inbred ICR , Morpholines/pharmacology , Naphthalenes/pharmacology , Nociception/drug effects , Pain/drug therapy , Pain/pathology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Terpenes/isolation & purification
2.
Sci Rep ; 10(1): 20405, 2020 11 23.
Article in English | MEDLINE | ID: mdl-33230154

ABSTRACT

The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, ßarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.


Subject(s)
Analgesics/pharmacology , Anti-Anxiety Agents/pharmacology , Cannabinoid Receptor Agonists/pharmacology , Cannabis/chemistry , Psychotropic Drugs/pharmacology , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB2/genetics , Analgesics/isolation & purification , Animals , Anti-Anxiety Agents/isolation & purification , CHO Cells , Cannabidiol/isolation & purification , Cannabidiol/pharmacology , Cannabinoid Receptor Agonists/isolation & purification , Cannabinoids/isolation & purification , Cannabinoids/pharmacology , Cricetulus , Dronabinol/analogs & derivatives , Dronabinol/isolation & purification , Dronabinol/pharmacology , Gene Expression , Humans , Mice, Inbred C57BL , Plant Extracts/chemistry , Psychotropic Drugs/isolation & purification , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Transgenes , beta-Arrestin 2/genetics , beta-Arrestin 2/metabolism
3.
Biomed Pharmacother ; 132: 110889, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33113429

ABSTRACT

The endocannabinoid system (ECS) is natural physiological system in the humans. The presence of the ECS system involves different roles in body. The endocannabinoid system involves regulation of most of the centers, which regulates the hunger and leads to changes in the weight. In the present article, we reviewed the role of natural cannabinoid compounds in metabolic disorders and related complications. We studied variety of a plant-derived cannabinoids in treating the metabolic syndrome including stoutness, fatty acid liver diseases, insulin obstruction, dementia, hypertension, lipid abnormalities, non-alcoholic steatohepatitis, endothelial damage, and polycystic ovarian syndrome and so on. The activation of cannabinoid receptors demonstrates a significant number of beneficial approaches concerning metabolic syndrome and reduces the pro-inflammatory cytokines on account of aggravation, decreased oxidative stress and uneasiness, diminishes liver fibrosis, with reduces adiponectin. Pre-clinical investigations of plant-derived cannabinoids resulted in promising outcomes. The different distinctive plant-derived cannabinoids were discovered like cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), and cannabidiol (CBG). It has been observed that endogenous cannabinoids and plant-derived cannabinoids have an advantageous impact on limiting the metabolic disorder arising due to lifestyle changes.


Subject(s)
Cannabinoid Receptor Agonists/therapeutic use , Cannabinoid Receptor Antagonists/therapeutic use , Cannabinoids/therapeutic use , Endocannabinoids/metabolism , Metabolic Syndrome/drug therapy , Plant Extracts/therapeutic use , Receptors, Cannabinoid/drug effects , Animals , Cannabinoid Receptor Agonists/adverse effects , Cannabinoid Receptor Agonists/isolation & purification , Cannabinoid Receptor Antagonists/adverse effects , Cannabinoid Receptor Antagonists/isolation & purification , Cannabinoids/adverse effects , Cannabinoids/isolation & purification , Drug Partial Agonism , Humans , Metabolic Syndrome/metabolism , Plant Extracts/adverse effects , Plant Extracts/isolation & purification , Plants, Medicinal , Receptors, Cannabinoid/metabolism , Signal Transduction
4.
J Cardiovasc Pharmacol Ther ; 25(6): 508-522, 2020 11.
Article in English | MEDLINE | ID: mdl-32588641

ABSTRACT

Phytogenic cannabinoids from Cannabis sativa and synthetic cannabinoids are commonly used substances for their recreational and medicinal properties. There are increasing reports of cardiotoxicity in close temporal association with cannabinoid use in patients with structurally normal hearts and absence of coronary arterial disease. Associated adverse events include myocardial ischemia, conduction abnormalities, arrhythmias, and sudden death. This review details the effects of phytogenic and synthetic cannabinoids on diverse receptors based on evidence from in vitro, human, and animal studies to establish a molecular basis for these deleterious clinical effects. The synergism between endocannabinoid dysregulation, cannabinoid receptor, and noncannabinoid receptor binding, and impact on cellular ion flux and coronary microvascular circulation is delineated. Pharmacogenetic factors placing certain patients at higher risk for cardiotoxicity are also correlated with the diverse effects of cannabinoids.


Subject(s)
Acute Coronary Syndrome/chemically induced , Arrhythmias, Cardiac/chemically induced , Cannabinoid Receptor Agonists/adverse effects , Cannabinoids/adverse effects , Cannabis/adverse effects , Heart/drug effects , Marijuana Abuse/complications , Marijuana Smoking/adverse effects , Acute Coronary Syndrome/physiopathology , Animals , Arrhythmias, Cardiac/physiopathology , Cannabinoid Receptor Agonists/chemical synthesis , Cannabinoid Receptor Agonists/isolation & purification , Cannabinoids/chemical synthesis , Cannabinoids/isolation & purification , Cannabis/chemistry , Cardiotoxicity , Heart/physiopathology , Heart Rate/drug effects , Humans , Receptors, Cannabinoid/drug effects , Risk Assessment , Risk Factors , Signal Transduction
5.
Molecules ; 25(7)2020 Mar 29.
Article in English | MEDLINE | ID: mdl-32235333

ABSTRACT

Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.


Subject(s)
Alzheimer Disease/drug therapy , Anxiety/drug therapy , Cannabinoid Receptor Agonists/chemistry , Cannabis/chemistry , Cognitive Dysfunction/drug therapy , Neuroprotective Agents/chemistry , Schizophrenia/drug therapy , Alzheimer Disease/physiopathology , Anxiety/physiopathology , Bicyclic Monoterpenes/chemistry , Bicyclic Monoterpenes/isolation & purification , Bicyclic Monoterpenes/pharmacology , Cannabidiol/chemistry , Cannabidiol/isolation & purification , Cannabidiol/pharmacology , Cannabinoid Receptor Agonists/classification , Cannabinoid Receptor Agonists/isolation & purification , Cannabinoid Receptor Agonists/pharmacology , Cognitive Dysfunction/physiopathology , Dronabinol/chemistry , Dronabinol/isolation & purification , Dronabinol/pharmacology , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/physiopathology , Neuralgia/drug therapy , Neuralgia/physiopathology , Neuroprotective Agents/classification , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/pharmacology , Nootropic Agents/chemistry , Nootropic Agents/classification , Nootropic Agents/isolation & purification , Nootropic Agents/pharmacology , Schizophrenia/physiopathology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Terpenes/chemistry , Terpenes/isolation & purification , Terpenes/pharmacology
6.
Biomed Pharmacother ; 106: 1317-1324, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30119202

ABSTRACT

BACKGROUND: This study aimed to investigate and characterize the anti-inflammatory and anti-hypernociceptive effects of the total polysaccharides of X. americana (TPL-Xa) bark in a mouse model of acute pancreatitis-induced by caerulein and the potential involvement of cannabinoid receptors. METHODS: TPL-Xa was characterized by1H and 13C NMR spectroscopy. Animals received TPL-Xa (10 mg/kg, i.v.) 30 min before and after caerulein (50 µg/kg, 10×, i.p.) administration. To evaluate the involvement of cannabinoid receptors, AM281 (3 mg/kg, s.c.) and AM630 (1 mg/kg, s.c.) were administered 30 min before TPL-Xa. Plasma levels of amylase and lipase, pancreatic myeloperoxidase (MPO), histology, visceral hypernociception and motor coordination were evaluated 11 and 24 h after acute pancreatitis (AP) induction. RESULTS: TPL-Xa, containing a heteropolysaccharide composed of glucose, galactose, arabinose, rhamnose, fucose and galacturonic acid, reduced amylase and lipase levels, MPO activity, acinar cell necrosis, edema and neutrophil infiltration. TPL-Xa increased the threshold of visceral hypernociception, an effect reversed by AM630, an antagonist of cannabinoid receptor type 2 (CB2). In addition, TPL-Xa did not alter the animals' motor coordination. CONCLUSIONS: TPL-Xa contains heteropolysaccharides that inhibit inflammation and hypernociception in the experimental model of caerulein-induced AP, by a mechanism involving type CB2 receptors.


Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Cannabinoid Receptor Agonists/pharmacology , Ceruletide , Nociceptive Pain/prevention & control , Olacaceae , Pancreas/drug effects , Pancreatitis/prevention & control , Plant Extracts/pharmacology , Polysaccharides/pharmacology , Receptor, Cannabinoid, CB2/agonists , Analgesics/isolation & purification , Animals , Anti-Inflammatory Agents/isolation & purification , Cannabinoid Receptor Agonists/isolation & purification , Carbon-13 Magnetic Resonance Spectroscopy , Disease Models, Animal , Enzymes/blood , Inflammation Mediators/metabolism , Male , Mice , Motor Activity/drug effects , Nociceptive Pain/chemically induced , Nociceptive Pain/metabolism , Olacaceae/chemistry , Pain Threshold/drug effects , Pancreas/enzymology , Pancreas/pathology , Pancreatitis/chemically induced , Pancreatitis/metabolism , Pancreatitis/pathology , Phytotherapy , Plant Extracts/isolation & purification , Plants, Medicinal , Polysaccharides/isolation & purification , Proton Magnetic Resonance Spectroscopy , Receptor, Cannabinoid, CB2/metabolism , Signal Transduction/drug effects , Time Factors
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