scholarly journals Early Cannabinoid Exposure as a Source of Vulnerability to Opiate Addiction: A Model in Laboratory Rodents

1998 ◽  
Vol 1 ◽  
pp. 39-58 ◽  
Author(s):  
Miguel Navarro ◽  
Fernando Rodríguez de Fonseca
Keyword(s):  
Brain Function ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Adult Brain ◽  
Opiate Abuse ◽  
Laboratory Rodents ◽  
Endogenous Cannabinoid ◽  
Arachidonoyl Glycerol ◽  
The Brain ◽  
Endogenous Cannabinoid System

Recent findings have identified an endogenous brain system mediating the actions of cannabis sativa preparations. This system includes the brain cannabinoid receptor (CB-1) and its endogenous ligands anandamide and 2-arachidonoyl-glycerol. The endogenous cannabinoid system is not only present in the adult brain, but is also active at early stages of brain development. Studies developed at our laboratory have revealed that maternal exposure to psychoactive cannabinoid results in neuro-developmental alterations. A model is proposed in which early Δ9-tetrahydrocannabinol (THC) exposure during critical developmental periods results in permanent alterations in brain function by either the stimulation of CB-1 receptors present during the development, or by the alterations in maternal glucocorticoid secretion. Those alterations will be revealed in adulthood after challenges either with drugs (i.e. opiates) or with environmental stressors (i.e. novelty). They will include a modified pattern of neuro-chemical, endocrine, and behavioral responses that might lead ultimately to inadaptation and vulnerability to opiate abuse.

scholarly journals The endogenous cannabinoid system

e-Neuroforum ◽  
2012 ◽  
Vol 18 (4) ◽  
Author(s):  
E. Drews ◽  
A. Zimmer
Keyword(s):  
Pain Perception ◽  
Cannabis Sativa ◽  
Feedback Mechanism ◽  
New Drugs ◽  
Active Components ◽  
Cannabinoid System ◽  
Medical Plant ◽  
Endogenous Cannabinoid ◽  
The Brain ◽  
Endogenous Cannabinoid System

AbstractThe hemp plant Cannabis sativa has been cultivated for thousands of years and is used as a medical plant and intoxicant. Scientif­ic research on the psychoactive substances of Cannabis sativa and their effects on the brain started around 50 years ago and led to the discovery of the endogenous cannabi­noid system. Today we know that this system represents an important feedback mechanism that modulates the communication be­tween neurons. However, this system is not only active in the brain, but is known to be activated in different tissues and organs during specific disease states. Consequently, there is increasing interest in this system as a possible target for the development of new drugs. The currently commercially available drugs are based on cannabis extracts or synthetic compounds of the plant’s active components and are mainly used to treat chron­ic pain. In this review, the mechanisms of the endogenous cannabinoid system in pain perception are elucidated and a new herbal (phyto)cannabinoid which is a constituent of our daily food is presented.

scholarly journals Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation

2018 ◽  
Vol 36 (2) ◽  
Author(s):  
Andrea Mastinu ◽  
Marika Premoli ◽  
Giulia Ferrari-Toninelli ◽  
Simone Tambaro ◽  
Giuseppina Maccarinelli ◽  
...  
Keyword(s):  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Receptor Type ◽  
History Of ◽  
Health And Disease ◽  
Pharmacological Potential ◽  
The Brain ◽  
Synthesis And Degradation

Abstract The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena. In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving. Moreover, cannabinoid agonists are able to reduce inflammatory response. In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made. Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.

scholarly journals Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

2017 ◽  
Vol 114 (25) ◽  
pp. E5006-E5015 ◽  
Author(s):  
Andrea Chicca ◽  
Simon Nicolussi ◽  
Ruben Bartholomäus ◽  
Martina Blunder ◽  
Alejandro Aparisi Rey ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Cannabinoid Receptor ◽  
Facilitated Diffusion ◽  
Chemical Probes ◽  
Analgesic Effects ◽  
Complex Process ◽  
Arachidonoyl Glycerol ◽  
The Brain

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derivedN-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50= 10 nM) inhibitorN-(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

scholarly journals Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

2021 ◽  
Author(s):  
Marc Ten-Blanco ◽  
África Flores ◽  
Inmaculada Pereda-Pérez ◽  
Fabiana Piscitelli ◽  
Cristina Izquierdo-Luengo ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Cannabinoid Receptor ◽  
Fear Extinction ◽  
Post Traumatic Stress ◽  
Orexin A ◽  
Post Traumatic ◽  
Learned Fear ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

Background and purpose: Anxiety is often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear remain unknown. Experimental approach: We investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. Behavioural pharmacology, neurochemical, molecular and genetic approaches were used. Key results: The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. Conclusions and implications: We reveal that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism may pave the way towards novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.

scholarly journals “Every cloud …”

2000 ◽  
Vol 176 (5) ◽  
pp. 412-413 ◽  
Author(s):  
Ian H. Robertson
Keyword(s):  
Early Childhood ◽  
Brain Function ◽  
Clinical Work ◽  
Adult Brain ◽  
Monday Morning ◽  
Dinner Party ◽  
Work Related ◽  
The Common ◽  
Plastic Changes ◽  
The Brain

Those involved in research or clinical work related to brain function will be used to the dinner party question “we only use 50% of the brain, don't we?” The scientist's dismissive sneer is usually well enough concealed, depending on how much he or she has had to drink. Where on earth did this lay myth arise, we chuckle over coffee in the common room on Monday morning? But scientists and clinicians are not immune to myths also. For many decades, neuroscientists preached the doctrine that the adult brain is ‘hard-wired’. Perhaps in very early childhood, we conceded, plastic changes in the brain were possible, but after the age of three or four years connections were indelibly made.

scholarly journals Different Effects of Cannabis Abuse on Adolescent and Adult Brain

Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 609-617
Author(s):  
Stefan Dhein
Keyword(s):  
Grey Matter ◽  
Structural Changes ◽  
Cannabis Sativa ◽  
Adult Brain ◽  
Cannabis Abuse ◽  
The Past ◽  
Neuronal Growth Factor ◽  
Culturing Conditions ◽  
Neuronal Conversion ◽  
The Brain

Cannabis abuse is a common phenomenon among adolescents. The dominant psychoactive substance in <i>Cannabis sativa</i> is tetrahydrocannabinol (THC). However, in the past 40 years the content of the psychoactive ingredient THC in most of the preparations is not constant but has increased due to other breeding and culturing conditions. THC acts as the endocannabinoids at CB1 and CB2 receptors but pharmacologically can be described as a partial (not a pure) agonist. Recent evidence shows that activation of the CB1 receptor by THC can diminish the production of neuronal growth factor in neurons and affect other signalling cascades involved in synapsis formation. Since these factors play an important role in the brain development and in the neuronal conversion processes during puberty, it seems reasonable that THC can affect the adolescent brain in another manner than the adult brain. Accordingly, in adolescent cannabis users structural changes were observed with loss of grey matter in certain brain areas. Moreover, recent studies show different effects of THC on adolescent and adult brains and on behaviour. These studies indicate that early THC abuse can result in neuropsychological deficits. This review gives an overview over the present knowledge in this field.

scholarly journals Cannabis sativa and the Endogenous Cannabinoid System: Therapeutic Potential for Appetite Regulation

2011 ◽  
Vol 25 (2) ◽  
pp. 170-188 ◽  
Author(s):  
Jonathan A. Farrimond ◽  
Marion S. Mercier ◽  
Benjamin J. Whalley ◽  
Claire M. Williams
Keyword(s):  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Appetite Regulation ◽  
Cannabinoid System ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

scholarly journals Modulation of Fear and Anxiety by the Endogenous Cannabinoid System

CNS Spectrums ◽  
2007 ◽  
Vol 12 (3) ◽  
pp. 211-220 ◽  
Author(s):  
Jasmeer P. Chhatwal ◽  
Kerry J. Ressler
Keyword(s):  
Cannabinoid Receptor ◽  
Conditioned Fear ◽  
Neural Circuitry ◽  
Cannabinoid System ◽  
Fear And Anxiety ◽  
New Treatments ◽  
Endogenous Cannabinoid ◽  
Remarkable Progress ◽  
Endogenous Cannabinoid System

ABSTRACTThe last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.

scholarly journals Cannabinoid signaling in health and disease

2017 ◽  
Vol 95 (4) ◽  
pp. 311-327 ◽  
Author(s):  
Yan Lu ◽  
Hope D. Anderson
Keyword(s):  
Side Effects ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Receptor Signaling ◽  
Safety And Efficacy ◽  
Health And Disease ◽  
Endogenous Cannabinoid ◽  
Umbrella Group

Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.

scholarly journals The Endocannabinoid System of Animals

2019 ◽  
Author(s):  
Robert Silver
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Mammalian Species ◽  
Endocannabinoid System ◽  
Precise Determination ◽  
Organ Systems ◽  
Protein Receptors ◽  
Ubiquitous System ◽  
Arachidonoyl Glycerol

The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species primitive as the Hydra. Insects apparently are devoid of this otherwise ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts: 1. Endogenous ligands, 2. G-protein coupled receptors (GPCRs), and 3. Enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. These are the endocannabinoids: Anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed, phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.

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