Direct inhibition by cannabinoids of human 5‐HT<sub>3A</sub> receptors: probable involvement of an allosteric modulatory site

Barann, Martin; Molderings, Gerhard J.; Brüss, Michael; Bönisch, Heinz; Urban, B. W.; Göthert, M.

doi:10.1038/sj.bjp.0704829

Cited by 212 publications

(193 citation statements)

References 43 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…The anatomical and neurochemical substrates of delayed-phase emesis have yet to be elucidated, although recent work points towards NK-1 neurokinin receptor activation by Substance P [5,12,46,48] and/or 5-HT4R activation by 5-HT [36]. In addition, significant evidence has been collected for both pro-emetic [14,27] and anti-emetic roles [2,12,13,27,44,50,51] for cannabinoid-related activity.…”

Section: Introductionmentioning

confidence: 99%

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

Ray

Darmani

2007

Brain Research

View full text Add to dashboard Cite

Chemotherapy is an effective treatment but difficult to tolerate due to side effects like vomiting. Studies on the etiology of chemotherapy-related emesis have implicated brainstem nuclei and the neurotransmitter Substance P, among other substrates. Since rodents do not vomit, other species have been necessary as alternative models of chemotherapy-induced emesis. Of these, the least shrew (Cryptotis parva) has proven valuable due to its small size, hardiness, and close phylogenetic relationship with primates. However, very little neuroanatomical data on C. parva exist. We used histological and immunohistochemical techniques to provide neuroanatomical data to help validate C. parva as a model organism, especially for emesis research. Brains were sectioned and stained for Nissl substance or myelin, or immunofluorescently labeled for Substance P. Sections were photographed, traced, and reconstructed with standardized zero points, and these data used to create a stereotaxic atlas. The brain of C. parva was similar to but smaller than other mammalian brains, with the cerebellum and hippocampus demonstrating the biggest differences. Differences appeared to be related to the small size of the brain and the metabolic compromises required of such a small mammal. Substance P-like immunoreactivity (SPL-IR) was semiquantitatively mapped, and correlated very well with SPL-IR observed in other species. Dense SPL-IR areas included the periaqueductal grey, trigeminal nuclei, dorsal raphe, and emesis-related brainstem nuclei including the area postrema and solitary tract nucleus. These data demonstrate that the anatomical differences between C. parva and other mammals will not preclude its use as a model organism.

show abstract

Section: Introductionmentioning

confidence: 99%

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

Ray

Darmani

2007

Brain Research

View full text Add to dashboard Cite

show abstract

“…Identification of a specific binding site for the phytocannabinoid, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) (7), cloning of the cannabinoid receptors (CB 1 and CB 2 ) (8,9), and the identification of an endogenous ligand, anandamide (N-arachidonoylethanolamide) (10), provided evidence of an endogenous cannabinoid system. Anandamide represents a class of lipid neurotransmitters that stimulate not only presynaptic and postsynaptic CB 1 receptors but also TRPV1 ion channels (11,12), 5-hydroxytryptamine receptors (13)(14)(15)(16), and possibly other receptors, as well as CB 2 receptors in the periphery (10,(17)(18)(19). More recently, the enzymes that are responsible for anandamide synthesis (phospholipase D) and catabolism (fatty acid amide hydrolase, FAAH) have been identified and characterized (20,21).…”

mentioning

confidence: 99%

Identification of a high-affinity binding site involved in the transport of endocannabinoids

Moore

Nomikos²,

Dickason-Chesterfield³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

153

View full text Add to dashboard Cite

Phytocannabinoids, such as the principal bioactive component of marijuana, ⌬ 9 -tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. ⌬ 9 -Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB 1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC 50 7.27 ؎ 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K d ‫؍‬ 7.62 ؎ 1.18 nM, Bmax ‫؍‬ 31.6 ؎ 1.80 fmol͞mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.anandamide ͉ fatty acid amide hydrolase ͉ cannabinoid ͉ marijuana ͉ transporter E ndocannabinoids are recognized as significant intracellular lipid signaling molecules in the central nervous system with extensive control of physiological and behavioral mood and affect. Increases in endocannabinoid neurotransmission have broad therapeutic potential, including reduction of nausea and emesis (1), appetite stimulation (2), analgesia (3), anxiolytic activity (4), antispasmodic activity (5), and lowering of intraocular pressure in glaucoma (6). Identification of a specific binding site for the phytocannabinoid, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) (7), cloning of the cannabinoid receptors (CB 1 and CB 2 ) (8, 9), and the identification of an endogenous ligand, anandamide (N-arachidonoylethanolamide) (10), provided evidence of an endogenous cannabinoid system. Anandamide represents a class of lipid neurotransmitters that stimulate not only presynaptic and postsynaptic CB 1 receptors but also TRPV1 ion channels (11, 12), 5-hydroxytryptamine receptors (13-16), and possibly other receptors, as well as CB 2 receptors in the periphery (10,(17)(18)(19). More recently, the enzymes that are responsible for anandamide synthesis (phospholipase D) and catabolism (fatty acid amide hydrolase, FAAH) have been identified and characterized (20,21). Unlike typical neurotransmitter molecules, anandamide is synthesized in the membrane bilayer, resulting in the phospholipid precursor of anandamide, Narachidonoylphosphatidylethanolamine (22-25). Calciumacti...

show abstract

“…It is clear that the complicated pharmacological characteristics of cannabinoids continue to puzzle and fascinate. (Barann, 2002): D 9 -THC5WIN-55,212-25 anandamide4CP-55,940 CB 1 (Felder et al, 1995): CP-55,9404D 9 -THC5 WIN-55,212-25anandamide CB 2 (Felder et al, 1995) …”

mentioning

confidence: 99%

Cannabinoids throw up a conundrum

Townsend¹,

Thayer²,

Brown³

2002

British J Pharmacology

View full text Add to dashboard Cite

The principal biologically active constituent of cannabis, D 9 -tetrahydrocannabinol (THC) and its synthetic analogues decrease neuronal signalling in the central, peripheral and enteric nervous systems (Martin, 2002). Some neural e ects produced by cannabinoids have potential clinical bene®ts, such as their analgesic and antiemetic actions. In the past decade, several arachidonic acid derivatives such as anandamide and 2-arachidonoylglycerol have been identi®ed as endogenous activators of two G protein-coupled cannabinoid receptors. Postsynaptic activity stimulates endocannabinoid synthesis, resulting in a retrograde action of endocannabinoids on cannabinoid receptors located on presynaptic terminals. Through the use of cannabinoid receptor knockout animals and the development of selective receptor antagonists, it has been possible to link many of the behavioural and peripheral e ects of cannabinoids to actions on the endocannabinoid system. Although cannabinoid receptors have been cloned and are well-characterized, pharmacological studies with cannabinoid ligands have continued to present conundrums. Some of the neuronal, cardiovascular and gastrointestinal actions of cannabinoids have been ascribed to mechanisms independent of cannabinoid CB 1 and CB 2 receptors (Kunos et al., 2000;Zygmunt et al., 2002). Moreover, anandamide appears to act as an agonist at vanilloid VR 1 receptors (Smart et al., 2000). Finally, the cannabimimetic eicosanoids, THC derivatives (such as CP-55,940) and aminoalkylindole-based cannabinoids (WIN-55,212-2 is an example) inhibit 5-HT evoked depolarization of rat nodose ganglion neurones. This e ect could not be attributed to cannabinoid receptors or indeed to a G protein-coupled receptor, but rather to the ionotropic 5-HT 3 receptor (Fan, 1995).Using 5-HT 3A receptor subunits expressed in HEK 293 cells, Barann et al. (this issue, 2002) report compelling evidence that cannabinoids allosterically modulate this ligand-gated ion channel. Chemically dissimilar cannabinoid agonists inhibited 5-HT-induced cation conductance with a rank order of potency that di ered from their potencies in stimulating cannabinoid receptors (Table 1). Moreover, the inhibitory actions of WIN-55,212 were resistant to the cannabinoid CB 1 receptor antagonist, SR-141716A and the presence of speci®c cannabinoid binding sites was not detected in HEK 293 cells. These results suggest that the inhibitory actions of cannabinoids are not mediated by cannabinoid receptors, yet their actions were potent and stereoselective. Thus, these lipophilic drugs appear to exert their actions directly on the 5-HT 3A receptor through a novel modulatory site.This modulatory action is non-competitive in nature, as pre-treatment of the recombinant 5-HT 3A receptor with the cannabinoid agonist WIN55,212-2 results in a suppression of the maximal current evoked by 5-HT. The mechanism of this antagonism is still not clear, although the required preincubation and the lack of use dependence would seem to rule out an open channel block. The al...

show abstract

Direct inhibition by cannabinoids of human 5‐HT_3A receptors: probable involvement of an allosteric modulatory site

Cited by 212 publications

References 43 publications

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

Identification of a high-affinity binding site involved in the transport of endocannabinoids

Cannabinoids throw up a conundrum

Contact Info

Product

Resources

About

Direct inhibition by cannabinoids of human 5‐HT3A receptors: probable involvement of an allosteric modulatory site

Cited by 212 publications

References 43 publications

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

Identification of a high-affinity binding site involved in the transport of endocannabinoids

Cannabinoids throw up a conundrum

Contact Info

Product

Resources

About

Direct inhibition by cannabinoids of human 5‐HT_3A receptors: probable involvement of an allosteric modulatory site