CB1 and CB2 Receptor Expression and Promoter Methylation in Patients with Cannabis Dependence

Rotter, Andrea; Bayerlein, Kristina; Hansbauer, Max; Weiland, Judith; Sperling, Wolfgang; Kornhuber, Johannes; Biermann, Teresa

doi:10.1159/000338642

Cited by 56 publications

(44 citation statements)

References 76 publications

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“…Finally, it is unlikely that the increased CB 2 expression is due to cannabis since most of our participants did not report using it regularly. Notably, two previous studies reported no changes of CB 2 expression in immune cells in cannabis users compared to non‐users …”

Section: Discussionmentioning

confidence: 89%

µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

Dothel

Chang

Shih

et al. 2019

Neurogastroenterology Motil

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Background and Aims The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ‐opioid receptor (MOR), its ligand β‐endorphin (β‐END), and cannabinoid receptor‐2 (CB2) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception. Methods Mucosal biopsies were obtained from the left colon of 31 IBS patients (45% women) with predominant constipation (IBS‐C, 9) or diarrhea (IBS‐D, 10) or with mixed bowel habits (IBS‐M, 12) and 32 AC (44% women) and processed for qRT‐PCR, Western blotting, and immunohistochemistry. Key Results µ‐opioid receptor and CB2 mRNA and protein expression and β‐END protein levels were increased in patients with IBS compared to AC (all Ps=0.021). A significant sex by IBS interaction was found in relation to CB2 mRNA expression (P = .003) with women showing a markedly higher expression to men (P = .035). In contrast, in AC, men had higher expression than women (P = .033). β‐END, MOR, and CB2 immunoreactivities (IR) were localized to CD4+T cells including EMR‐1+ eosinophils and CD31+ T cells but not to mast cells. Conclusions The increased expression of MOR, β‐END, and CB2 in the mucosa of IBS patients, where they are localized to immune cells, suggests that opioid and cannabinoid systems play an immune‐related compensatory role in visceral pain in IBS patients. Further work is necessary to support this hypothesis.

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Section: Discussionmentioning

confidence: 89%

µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

Dothel

Chang

Shih

et al. 2019

Neurogastroenterology Motil

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“…Variable downregulation in different brain regions may explain why frequent users of cannabis develop tolerance to some effects of THC, such as anxiogenesis and cognitive impairment, but not to its euphoric effects [291]. Downregulation is partially epigenetic—the CB 1 promoter region in chronic marijuana smokers is hypermethylated, reducing CB 1 mRNA expression levels [292].…”

Section: Resultsmentioning

confidence: 99%

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

2014

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BackgroundThe “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.Methodology/Principal FindingsWe searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.Conclusions/SignificanceFew clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

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“…Several studies implicate increased epigenetic influences following chronic Δ9-THC exposure. Marijuana dependent patients present robust methylation of the CNR1 promoter in association with diminished CNR1 mRNA in peripheral blood cells 196 . Further, offspring of maternal marijuana users exhibit histone methylation and dysregulated mesolimbic dopamine D 2 receptor Drd2 expression 197 and adolescent Δ9-THC exposure is associated with NAc chromatin modifications and concurrent upregulation of the opioid neuropeptide proenkephalin gene 198 .…”

Section: Endocannabinoid Signaling In Addictionmentioning

confidence: 98%

Endocannabinoid signalling in reward and addiction

2015

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Brain endocannabinoid signaling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated endocannabinoid signaling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired endocannabinoid signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states, and craving that propel addiction. Understanding the contributions of endocannabinoid disruptions to behavioral and physiological traits provides insight into the endocannabinoid influence on addiction vulnerability.

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CB1 and CB2 Receptor Expression and Promoter Methylation in Patients with Cannabis Dependence

Cited by 56 publications

References 76 publications

µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Endocannabinoid signalling in reward and addiction

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