BACKGROUND AND PURPOSECannabidiol has been reported to act as an antagonist at cannabinoid CB 1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB 1 receptors. EXPERIMENTAL APPROACHInternalization of CB 1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB 1 receptors and in the STHdh Q7/Q7 cell model of striatal neurons endogenously expressing CB 1 receptors. Cells were treated with 2-arachidonylglycerol or Δ 9 -tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. KEY RESULTSCannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ 9 -tetrahydrocannabinol on PLCβ3-and ERK1/2-dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdh Q7/Q7 ) expressing CB 1 receptors. By reducing arrestin2 recruitment to CB 1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB 1 receptor. CONCLUSIONS AND IMPLICATIONSCannabidiol behaved as a non-competitive negative allosteric modulator of CB 1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB 1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB 1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.

Background:The Pfizer-BioNTech COVID-19 vaccine has recently received emergency approval from the US FDA. The mRNA technology was used to manufacture the Pfizer vaccine; however, as a pioneering technology that has never been used in the manufacture of vaccines, many people have concerns about the vaccine's side effects. Thus, the current study aimed to track the short-term side effects of the vaccine. Methods: The information in this study was gathered by a Google Form-questionnaire (online survey). The results included the responses of 455 individuals, all of whom are Saudi Arabia inhabitants. Adverse effects of the vaccine were reported after the first and the second doses. Results: The most common symptoms were injection site pain, headaches, flu-like symptoms, fever, and tiredness. Less common side effects were a fast heartbeat, whole body aches, difficulty breathing, joint pain, chills, and drowsiness. Rare side effects include Bell's palsy and lymph nodes swelling and tenderness. Flu-like symptoms were more common among those under 60 years of age, while injection site pain was more frequent among recipients who were 60 years and older. The study revealed a significant increase in the number of females who suffered from the vaccine side effects compared to males. Difficulty of breathing was more reported among recipients who had been previously infected with the coronavirus compared to those who had not been previously infected. Conclusion: Most of the side effects reported in this study were consistent with Pfizer's fact sheet for recipients and caregivers. Further studies are required to determine the long-term side effects.

Background:To understand the differential response to cannabinoids, we examined the functional selectivity of type 1 cannabinoid receptor (CB 1 ) agonists in a cell model of striatal neurons. Results: 2-Arachidonylglycerol, ⌬ 9 -tetrahydrocannabinol, and CP55,940 were arrestin2-selective; endocannabinoids and WIN55,212-2 activated G␣ i/o , G␤␥, and G␣ q ; and cannabidiol activated G␣ s independent of CB 1 . Conclusion: Cannabinoids displayed functional selectivity. Significance: CB 1 functional selectivity may be exploited to maximize therapeutic efficacy.

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB 1 ) decrease in the basal ganglia. Decreasing CB 1 levels are strongly correlated with chorea and cognitive deficit. CB 1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh Q7/Q7 ) or mutant huntingtin protein (STHdh Q111/Q111). Signaling bias was assessed using the Black and Leff operational model. Relative activity [DlogR (t/K A )] and system bias (DDlogR) were calculated relative to the reference compound WIN55,212-2 for Ga i/o , Ga s , Ga q , Gbg, and b-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, D 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and THC1CBD (1:1), and compared between wild-type and HD cells. The E max of Ga i/o -dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Ga i/o /Gbg bias and normalized CB 1 protein levels and improved cell viability, whereas CP55,940 and THC displayed b-arrestin1 bias and reduced CB 1 protein levels and cell viability in HD cells. CBD was not a CB 1 agonist but inhibited THC-dependent signaling (THC1CBD). Therefore, enhancing Ga i/o -biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are b-arrestin-biased-such as THC found at high levels in modern varieties of marijuana-may be detrimental to CB 1 signaling, particularly in HD where CB 1 levels are already reduced.

No abstract