Endocannabinoid Receptor System Research Articles

1.3 Impact of Prenatal Cannabis Exposure on Neonatal Brain Connectivity

Cannabis use during pregnancy has been increasing, particularly with widening legalization of cannabis. Tetrahydrocannabinol (THC) readily passes the placenta, and the endocannabinoid receptor system is fully developed in the first trimester with cannabinoid receptors prevalent in regions important for social-emotional development including the amygdala, hippocampus, and medial prefrontal cortex. How cannabis use is impacting the structure and function of the neonatal brain, particularly with the higher potency of cannabis that is currently used, remains unclear.

Neurodevelopmental outcomes and prenatal exposure to marijuana.

BACKGROUND: Increased use of marijuana in pregnancy (3.9% in 2014 compared with 2.4% in 2002 in a recent self-reported survey) is a significant problem and poses potential health risks for the developing fetus. Studies have shown that the fetal endocannabinoid receptor system may be vulnerable to intrauterine exposure to THC (Tetrahydrocannabinol) and may produce long-term consequences on behavior and psychopathology in children. There are, however, limited studies evaluating the impact of prenatal marijuana use …

Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

Use of exogenous cannabinoids disrupts the fine-tuned endocannabinoid receptor system, possibly leading to alterations in cognition, memory, and emotional processes that endure long after cannabinoid use has stopped. Long-term adolescent use may uniquely disrupt these behaviors when compared to adult use. The current study explored the acute and long-term behavioral effects of six 10mg/kg Δ9-tetrahydrocannabinol (THC) injections across the adolescent or early adult period in male inbred C57Bl/6J and DBA/2J mice. The acute and prolonged effects of THC on object memory using the novel object recognition task, unconditioned anxiety in the elevated plus maze and open field, and sedative effects in the open field were examined. Acute THC treatment resulted in anxiogenic activity in both strains, but only caused sedation in B6 mice. Repeated THC treatment resulted in a protracted effect on object recognition, but not unconditioned anxiety, assessed 4weeks later. In both strains, an adolescent history of THC treatment disrupted later object recognition. Interestingly, in B6 mice an adult history of THC exposure appeared to rescue a deficit in object recognition observed in vehicle-treated adults. Repeated THC administration also produced a protracted effected on CB1R protein expression. Animals treated with THC in adolescence maintained increased levels of CB1R protein expression compared to their adult THC-treated counterparts at five weeks following the last injection. These results indicate that THC use may have long-lasting effects with adolescence being a unique period of susceptibility.

Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature.

The aetiology of obesity has been attributed to several factors (environmental, dietary, lifestyle, host, and genetic factors); however none of these fully explain the increase in the prevalence of obesity worldwide. Gut microbiota located at the interface of host and environment in the gut are a new area of research being explored to explain the excess accumulation of energy in obese individuals and may be a potential target for therapeutic manipulation to reduce host energy storage. Several mechanisms have been suggested to explain the role of gut microbiota in the aetiology of obesity such as short chain fatty acid production, stimulation of hormones, chronic low-grade inflammation, lipoprotein and bile acid metabolism, and increased endocannabinoid receptor system tone. However, evidence from animal and human studies clearly indicates controversies in determining the cause or effect relationship between the gut microbiota and obesity. Metagenomics based studies indicate that functionality rather than the composition of gut microbiota may be important. Further mechanistic studies controlling for environmental and epigenetic factors are therefore required to help unravel obesity pathogenesis.

Dynamic changes to the endocannabinoid system in models of chronic pain

The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls

BackgroundThe development of the fetal endocannabinoid receptor system may be vulnerable to maternal cannabis use during pregnancy and may produce long-term consequences in children. In this study, we aimed to determine the relationship between gestational cannabis use and childhood attention problems and aggressive behavior. MethodsUsing a large general population birth cohort, we examined the associations between parental prenatal cannabis and tobacco use and childhood behavior problems at 18 months measured using the Child Behavior Checklist in N=4077 children. Substance use was measured in early pregnancy. ResultsLinear regression analyses demonstrated that gestational exposure to cannabis is associated with behavioral problems in early childhood but only in girls and only in the area of increased aggressive behavior (B=2.02; 95% CI: 0.30–3.73; p=0.02) and attention problems (B=1.04; 95% CI: 0.46–1.62; p<0.001). Furthermore, this study showed that long-term (but not short term) tobacco exposure was associated with behavioral problems in girls (B=1.16; 95% CI: 0.20–2.12; p=0.02). There was no association between cannabis use of the father and child behavior problems. ConclusionsOur results suggest that intrauterine exposure to cannabis is associated with an increased risk for aggressive behavior and attention problems as early as 18 months of age in girls, but not boys. Further research is needed to explore the association between prenatal cannabis exposure and child behavior at later ages. Our data support educating future mothers about the risk to their babies should they smoke cannabis during pregnancy.

Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain

ObjectiveTo investigate the impact of an experimental model of osteoarthritis (OA) on spinal nociceptive processing and the role of the inhibitory endocannabinoid system in regulating sensory processing at the spinal level.MethodsExperimental OA was induced in rats by intraarticular injection of sodium mono-iodoacetate (MIA), and the development of pain behavior was assessed. Extracellular single-unit recordings of wide dynamic range (WDR) neurons in the dorsal horn were obtained in MIA-treated rats and saline-treated rats. The levels of endocannabinoids and the protein and messenger RNA levels of the main synthetic enzymes for the endocannabinoids (N-acyl phosphatidylethanolamine phospholipase D [NAPE-PLD] and diacylglycerol lipase α [DAGLα]) in the spinal cord were measured.ResultsLow-weight (10 gm) mechanically evoked responses of WDR neurons were significantly (P < 0.05) facilitated 28 days after MIA injection compared with the responses in saline-treated rats, and spinal cord levels of anandamide and 2-arachidonoyl glycerol (2-AG) were increased in MIA-treated rats. Protein levels of NAPE-PLD and DAGLα, which synthesize anandamide and 2-AG, respectively, were elevated in the spinal cords of MIA-treated rats. The functional role of endocannabinoids in the spinal cords of MIA-treated rats was increased via activation of cannabinoid 1 (CB1) and CB2 receptors, and blockade of the catabolism of anandamide had significantly greater inhibitory effects in MIA-treated rats compared with control rats.ConclusionOur findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB2 receptors suggests that this receptor system may be an important target for the modulation of pain in OA.

Dynamic regulation of the endocannabinoid system: implications for analgesia.

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia

Highlighting the association between schizophrenia and Cannabis sativa and the endogenous cannabinoid receptor system, respectively, two opposite aspects are of major relevance. On the one hand, cannabis is the most widely used illegal drug. There is substantial evidence that cannabis has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. This risk seems to be increased in genetically predisposed people and may depend on the amount of cannabis used. On the other hand, during the last few years, an endogenous cannabinoid receptor system (including two known cannabinoid [CB1 and CB2] receptors and five endogenous ligands) has been discovered. There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia (e.g., increased density of CB1 receptor binding and increased levels of cerebrospinal fluid endocannabinoid anandamide). Accordingly, beside the ‘dopamine hypothesis’ of schizophrenia, a ‘cannabinoid hypothesis’ has been suggested. Interestingly, there is a complex interaction between the dopaminergic and the endocannabinoid receptor system. Thus, agents that interact with the cannabinoid receptor system, such as the nonpsychoactive cannabidiol, might be beneficial in the treatment of psychosis.

Brain endocannabinoid system is involved in fluoxetine-induced anorexia

In order to describe the effects of chronic fluoxetine administration on the brain endocannabinoid system in lean and obese Zucker rats, brain immunostaining for the CB1 and CB1-phosphorylated cannabinoid receptors was carried out. Obese Zucker rats showed significantly increased the numbers of neural cells positively immunostained for the CB1-phosphorylated receptor in the striatum, compared to their lean litter-mates. Chronic fluoxetine administration decreased the number of neural cells immunostained for CB1-phosphorylated receptor in several striatal and hippocampal regions of obese Zucker rats, compared to controls treated with saline. In contrast, no change in CB1-phosphorylated receptor immunostaining was observed in fluoxetine-treated lean rats, with respect to controls. Taken together, these results suggest the involvement of the hippocampal and striatal endocannabinoid receptor system in fluoxetine-induced anorexia in lean and obese Zucker rats.

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

IntroductionCannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB1) and receptor 2 (CB2) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA.MethodsThirty-two OA and 13 RA patients undergoing total knee arthroplasty were included in this study. Clinical staging was conducted from x-rays scored according to Kellgren-Lawrence and Larsen scales, and synovitis of synovial biopsies was graded. Endocannabinoid levels were quantified in synovial fluid by liquid chromatography-mass spectrometry. The expression of CB1 and CB2 protein and RNA in synovial biopsies was investigated. Functional activity of these receptors was determined with mitogen-activated protein kinase assays. To assess the impact of OA and RA on this receptor system, levels of endocannabinoids in the synovial fluid of patients and non-inflamed healthy volunteers were compared. The activity of fatty acid amide hydrolase (FAAH), the predominant catabolic endocannabinoid enzyme, was measured in synovium.ResultsCB1 and CB2 protein and RNA were present in the synovia of OA and RA patients. Cannabinoid receptor stimulation of fibroblast-like cells from OA and RA patients produced a time-dependent phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2 which was significantly blocked by the CB1 antagonist SR141716A. The endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) were identified in the synovial fluid of OA and RA patients. However, neither AEA nor 2-AG was detected in synovial fluid from normal volunteers. FAAH was active in the synovia of OA and RA patients and was sensitive to inhibition by URB597 (3'-(aminocarbonyl) [1,1'-biphenyl]-3-yl)-cyclohexylcarbamate).ConclusionOur data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.