Endocannabinoid-Mediated Control of Synaptic Transmission

Physiological Reviews, Journal Year: 2009, Volume and Issue: 89(1), P. 309 - 380

Published: Jan. 1, 2009

The discovery of cannabinoid receptors and subsequent identification their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on actions the brain. Then, 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for also established concept how diffusible messengers modulate efficacy neural activity. last 7 years witnessed remarkable advances our understanding endocannabinoid system. It is now well accepted are released from postsynaptic neurons, activate presynaptic CB(1) receptors, cause transient long-lasting reduction neurotransmitter release. In this review, we aim to integrate current functions system, especially focusing control transmission We summarize recent electrophysiological studies carried out synapses various brain regions discuss regulated by signaling. Then refer anatomical subcellular distribution molecules involved these arranged around synapses. addition, make brief overview intracellular signaling, biochemical metabolism, behavioral roles system aspects functions.

Language: Английский

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Cannabidiol: State of the art and new challenges for therapeutic applications

Pharmacology & Therapeutics, Journal Year: 2017, Volume and Issue: 175, P. 133 - 150

Published: Feb. 22, 2017

Language: Английский

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Cannabinoids and the gut: New developments and emerging concepts

Pharmacology & Therapeutics, Journal Year: 2010, Volume and Issue: 126(1), P. 21 - 38

Published: Feb. 2, 2010

Language: Английский

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The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Proceedings of the National Academy of Sciences, Journal Year: 2009, Volume and Issue: 106(38), P. 16511 - 16516

Published: Sept. 4, 2009

GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and lysophosphatidylinositol (LPI). However, the physiological role of remains unknown. Given recent finding that cannabinoid receptors CB(1) CB(2) affect bone metabolism, we examined in biology. was expressed human mouse osteoclasts osteoblasts; expression higher than macrophage progenitors. Although agonists O-1602 LPI inhibited osteoclast formation vitro, these ligands stimulated polarization resorption vitro caused activation Rho ERK1/2. These stimulatory effects on function were attenuated generated from GPR55(-/-) macrophages antagonist cannabidiol (CBD). Furthermore, treatment mice with this non-psychoactive constituent cannabis significantly reduced vivo. Consistent ability suppress but stimulate function, histomorphometric microcomputed tomographic analysis long bones male revealed increased numbers morphologically inactive significant increase volume thickness trabecular presence unresorbed cartilage. data reveal physiology regulating number function. In addition, study also brings light an effect both endogenous ligand, LPI, constituent, CBD, turnover

Language: Английский

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N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor

BMC Neuroscience, Journal Year: 2010, Volume and Issue: 11(1)

Published: March 26, 2010

Microglia provide continuous immune surveillance of the CNS and upon activation rapidly change phenotype to express receptors that respond chemoattractants during damage or infection. These activated microglia undergo directed migration towards affected tissue. Importantly, molecular species chemoattractant encountered determines if with pro- anti-inflammatory behaviour, yet signaling molecules trigger remain poorly understood. The endogenous cannabinoid system regulates microglial via CB2 an as unidentified GPCR termed 'abnormal cannabidiol' (Abn-CBD) receptor. Abn-CBD is a synthetic isomer phytocannabinoid cannabidiol (CBD) inactive at CB1 receptors, but functions selective agonist this Gi/o-coupled GPCR. N-arachidonoyl glycine (NAGly) metabolite endocannabinoid anandamide acts efficacious GPR18. Here, we investigate relationship between NAGly, Abn-CBD, 'Abn-CBD' receptor, GPR18, BV-2 migration.Using Boyden chamber experiments, yellow tetrazolium (MTT) conversion, In-cell Western, qPCR immunocytochemistry show sub-nanomolar concentrations, potently drive cellular in both HEK293-GPR18 transfected cells, neither induce HEK-GPR55 non-transfected HEK293 wildtype cells. Migration effects are blocked attenuated systems by receptor antagonist O-1918, low efficacy agonists N-arachidonoyl-serine cannabidiol. NAGly promotes proliferation MAP kinases cells nanomolar concentrations - responses correlated migration. Additionally, GPR18 immunocytochemical staining abundant mRNA. demonstrates primary microglia, likewise, amounts mRNA.NAGly most effective lipid recruiter currently reported its mimic those Abn-CBD. data generated from study supports hypothesis previously marked potency acting on elicit migration, perhaps other MAPK-dependent phenomena advances our understanding lipid-based mechanisms employed actively recruit sites interest. It offers novel research avenue for developing therapeutics self-renewing population neuroregenerative alternatively, prevent accumulation misdirected, pro-inflammatory which contribute exacerbate neurodegenerative disease.

Language: Английский

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The GPR55 ligand L‐α‐lysophosphatidylinositol promotes RhoA‐dependent Ca²⁺signaling and NFAT activation

The FASEB Journal, Journal Year: 2008, Volume and Issue: 23(1), P. 183 - 193

Published: Aug. 29, 2008

The endogenous phospholipid l-alpha-lysophosphatidylinositol (LPI) was recently identified as a novel ligand for the orphan G protein-coupled receptor 55 (GPR55). In this study we define downstream signaling pathways activated by LPI in human embryonic kidney (HEK) 293 cell line engineered to stably express recombinant GPR55. We find that treatment with induces marked GPR55 internalization and stimulates sustained, oscillatory Ca(2+) release pathway, which is dependent on Galpha13 requires RhoA activation. then establish cascade leads efficient activation of NFAT (nuclear factor T cells) family transcription factors their nuclear translocation. Analysis cannabinoid activity at revealed no clear effect endocannabinoids anandamide 2-arachidonoylglycerol; however, classical CB(1) antagonist AM251 evoked GPR55-mediated signaling. Thus, potent efficacious GPR55, likely be key plasma membrane mediator LPI-mediated events changes gene expression.

Language: Английский

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The enigmatic pharmacology of GPR55

Trends in Pharmacological Sciences, Journal Year: 2009, Volume and Issue: 30(3), P. 156 - 163

Published: Feb. 22, 2009

Language: Английский

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Transdermal cannabidiol reduces inflammation and pain‐related behaviours in a rat model of arthritis

European Journal of Pain, Journal Year: 2015, Volume and Issue: 20(6), P. 936 - 948

Published: Oct. 30, 2015

Current arthritis treatments often have side-effects attributable to active compounds as well route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels.This study examined efficacy transdermal for reduction in pain, assessing any adverse effects a rat complete Freund's adjuvant-induced monoarthritic knee joint model. gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied 4 consecutive days after induction. Joint circumference immune cell invasion histological sections measured indicate level inflammation. Paw withdrawal latency (PWL) response noxious heat stimulation determined nociceptive sensitization, exploratory behaviour ascertained animal's activity level.Measurement concentration provided by absorption revealed linearity with 0.6-6.2 mg/day doses. Transdermal gel significantly reduced swelling, limb posture scores rating spontaneous infiltration thickening the synovial membrane dose-dependent manner. PWL recovered near baseline level. Immunohistochemical analysis spinal cord (CGRP, OX42) dorsal root ganglia (TNFα) reductions pro-inflammatory biomarkers. Results showed 62 effective Exploratory was not altered indicating limited effect on higher brain function.These data that topical therapeutic potential relief pain-related behaviours evident side-effects.

Language: Английский

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Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use

Journal of Clinical Medicine, Journal Year: 2019, Volume and Issue: 8(7), P. 989 - 989

Published: July 8, 2019

Cannabidiol (CBD) is ubiquitous in state-based medical cannabis programs and consumer products for complementary health or recreational use. CBD has intrinsic pharmacologic effects associated adverse drug events (ADEs) along with the potential pharmacokinetic pharmacodynamic drug–drug interactions (DDIs). Given use among patients complex conditions treatment regimens, as well its expanded use, awareness of safety issues needed. Prescribing information federally approved containing were reviewed. Data on ADEs DDIs extracted summarized. Nearly one-half users experienced ADEs, which displayed a general dose-response relationship. Common include transaminase elevations, sedation, sleep disturbances, infection, anemia. common biological targets implicated metabolism (e.g., CYP3A4/2C19) excretion P-glycoprotein), commonly used medication high. General clinical recommendations reducing substrate doses, monitoring finding alternative therapy should be considered, especially medically patients. both victim perpetrator own ADE profile. These considered risk-benefit assessment consumers made aware

Language: Английский

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Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms

Progress in Lipid Research, Journal Year: 2013, Volume and Issue: 53, P. 18 - 81

Published: Oct. 11, 2013

Language: Английский

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