Effects of Δ<sup>9</sup>‐tetrahydrocannabivarin on [<sup>35</sup>S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes

Dennis, Ian F.; Whalley, Benjamin J.; Stephens, Gary J.

doi:10.1038/bjp.2008.190

Cited by 34 publications

(43 citation statements)

References 27 publications

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“…A caveat to these data is that WIN55 may stimulate a non-CB 1 -mediated component of [ 35 S]GTP␥S binding (Breivogel et al, 2001). In the present study, WIN55 displayed a higher efficacy than CP55940 in stimulation of [ 35 S]GTP␥S binding in cerebellar membranes, as reported in some previous studies (Breivogel et al, 2003;Childers, 2006 (Dennis et al, 2008), and that WIN55 inhibition at IN-PC synapses is prevented by ⌬ 9 -THCV (Ma et al, 2008), arguing against WIN55 causing functional CB 1 -independent effects here. With regard to alternative receptor targets, it is of interest that CP55940, but not WIN55, is a ligand at GPR55, a lysophosphatidylinsoitol receptor, with some sensitivity to cannabinoids (Ross, 2009) 2008).…”

Section: Discussionsupporting

confidence: 61%

“…We first sought to extend studies to CB 1 receptors in native murine cerebellar membranes (Dennis et al, 2008). The CB receptor agonist CP55940 stimulated […”

Section: Resultsmentioning

confidence: 99%

“…35 S]GTP␥S binding experiments were performed as described previously (Horswill et al, 2007;Dennis et al, 2008). In brief, 10 g of membranes per reaction was incubated with 10 M GDP and 0.1 nM […”

Section: [ 35 S]gtp␥s Binding Assaysmentioning

confidence: 99%

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Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum

Wang¹,

Horswill²,

Whalley³

et al. 2010

Mol Pharmacol

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1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl] urea (PSNCBAM-1) has recently been described as a cannabinoid CB1 receptor allosteric antagonist associated with hypophagic effects in vivo; however, PSNCBAM-1 effects on CB 1 ligand-mediated modulation of neuronal excitability remain unknown. Here, we investigate PSNCBAM-1 actions on CB 1 receptor-stimulated guanosine 5Ј-O-(3-[ In electrophysiological studies, WIN55 and CP55940 reduced miniature inhibitory postsynaptic currents (mIPSCs) frequency but not amplitude. PSNCBAM-1 application alone had no effect on mIPSCs; however, PSNCBAM-1 pretreatment revealed agonist-dependent functional antagonism, abolishing CP55940-induced reductions in mIPSC frequency but having no clear effect on WIN55 actions. The CB 1 antagonist/inverse agonist N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-multipyrazole-3-carboxamide (AM251) increased mIPSC frequency beyond control; this effect was reversed by PSNCBAM-1. PSNCBAM-1 pretreatment also attenuated AM251 effects. Thus, PSNCBAM-1 reduced CB 1 receptor ligand functional efficacy in the cerebellum. The differential effect of PSNCBAM-1 on CP55940 versus WIN55 actions in [ 35 S]GTP␥S binding and electrophysiological studies and the attenuation of AM251 effects are consistent with the liganddependence associated with allosteric modulation. These data provide the first description of functional PSNCBAM-1 allosteric antagonist effects on neuronal excitability in the mammalian central nervous system (CNS). PSNCBAM-1 allosteric antagonism may provide viable therapeutic alternatives to orthosteric CB 1 antagonists/inverse agonists in the treatment of CNS disease.

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Section: Discussionsupporting

confidence: 61%

“…We first sought to extend studies to CB 1 receptors in native murine cerebellar membranes (Dennis et al, 2008). The CB receptor agonist CP55940 stimulated […”

Section: Resultsmentioning

confidence: 99%

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Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum

Wang¹,

Horswill²,

Whalley³

et al. 2010

Mol Pharmacol

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“…35 S]GTP␥S binding to mouse whole brain, cerebellar, and piriform cortical membranes with no activity in the absence of agonist (199,855). ⌬ 9 -THCV antagonizes the ability of ⌬ 9 -THC and other agonists to inhibit electrically evoked mouse vas deferens contractions (855).…”

mentioning

confidence: 99%

“…9 -THCV increases inhibitory neurotransmission (199) by increasing, in a GABA A antagonist-sensitive manner, the inhibitory postsynaptic currents at interneuron-Purkinje cell synapses, and decreases Purkinje's cell spike firing in the mouse cerebellum in vitro (500). These effects could be useful in spinocerebellar ataxias, a pharmacologically untreatable group of hyperexcitability disorders, although preclinical in vivo animal studies in this specific therapeutic area have yet to be undertaken (347).…”

mentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

339

317

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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

Farrimond

Mercier

Whalley

et al. 2011

Phytotherapy Research

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The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non‐Δ9tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa‐induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra‐, inter‐ and extra‐cellular mechanisms of action, we demonstrate that non‐Δ9tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential. Copyright © 2011 John Wiley & Sons, Ltd.

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Effects of Δ⁹‐tetrahydrocannabivarin on [³⁵S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes

Cited by 34 publications

References 27 publications

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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

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Effects of Δ9‐tetrahydrocannabivarin on [35S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes

Cited by 34 publications

References 27 publications

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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

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Effects of Δ⁹‐tetrahydrocannabivarin on [³⁵S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB₁ Receptor Modulation in the Cerebellum