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Cannabinoids Biology: The Search for New Therapeutic Targets

Eli Lilly and Co., Neuroscience Division, Indianapolis, IN 46285

	SUMMARY

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
Cannabinoids, in the form of marijuana plant extracts, have been used for thousands of years for a wide variety of medical conditions, ranging from general malaise and mood disorders to more specific ailments, such as pain, nausea, and muscle spasms. The discovery of tetrahydrocannabinol, the active principal in marijuana, and the identification and cloning of two cannabinoid receptors (i.e., CB₁ and CB₂) has subsequently led to biomedical appreciation for a family of endocannabinoid lipid transmitters. The biosynthesis and catabolism of the endocannabinoids and growing knowledge of their broad physiological roles are providing insight into potentially novel therapeutic targets. Compounds directed at one or more of these targets may allow for cannabinoid-based therapeutics with limited side effects and abuse liability.

	INTRODUCTION

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
Cannabis sativa, more commonly known as the marijuana plant, produces a complex mixture of medicinal substances that are collectively referred to as the cannabinoids. Despite the widespread use of marijuana and considerable research effort into its physiological actions, the biological mechanisms of the cannabinoids are just now beginning to be revealed with both expected and unexpected results. Marijuana’s most active component, tetrahydrocannabinol (⁹-THC) (1), acts in animals as an agonist at the cannabinoid family of G protein–coupled receptors (GPCRs) that currently contains two subtypes, CB₁ and CB₂ (Table 1). Following the cloning of the receptors for ⁹-THC (2–4), an endogenous lipid agonist for both the CB₁ and CB₂ receptors was discovered in mammals and named "anandamide," from the Sanskrit word ananda for inner bliss and tranquility (5). Additional endocannabinoids continue to be discovered that are also cannabimimetic in central and peripheral tissues (6–9).

	CANNABINOID PHARMACOLOGY

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
Marijuana has been used for thousands of years for both medicinal and recreational purposes, and yet only relatively recently have we begun to understand the basic mechanisms of its action in the brain and periphery. The phytocannabinoids derived from marijuana consist of over fifty potentially bioactive compounds; however, early cannabinoid research tended to focus on the principle bioactive component of marijuana, ⁹-THC (1). Once ingested, ⁹-THC generates seven major metabolites and approximately twenty-five potentially bioactive metabolites. The complexity of the compounds to which patients are exposed, in combination with the inconsistent dosing regiments inherent in smoking or ingestion, has made the interpretation of clinical trials with medical marijuana particularly challenging. Notwithstanding these challenges, there is little argument that exposure to ⁹-THC can offer medical benefits including anti-nausea and -emesis (30), appetite stimulation (31), analgesia (32), anxiolytic activity (33), anti-spasmodic activity (34), and lowering of intraocular pressure in glaucoma (35). However, psychotropic and addiction-related side effects have restricted its medicinal use. Less well-known but significant side effects of marijuana use include sedation, cognitive dysfunction, tachycardia, postural hypotension, dry mouth, ataxia, reduced fertility, and immunosuppression(36).

Until the last decade, the design of ⁹-THC-mimetic drugs concentrated on the development of triterpenoid cannabinoid agonists with appropriate metabolic stability and oral bioavailability but without significant side effects. In the early 1970s, Pfizer (New York, NY, USA) synthesized levonantrodol, a compound more potent than ⁹-THC, for the treatment of emesis associated with chemotherapy and postoperative pain. The development of levonantrodol was abandoned, however, owing to psychotropic side effects (e.g., dysphoria, dizziness, thought disturbance, and somnolence) that appeared coincident with efficacious doses. Eli Lilly and Company (Indianapolis, IN, USA) similarly produced the ⁹-THC analog, nabilone, which proved effective against nausea and vomiting in chemotherapy as well as anesthesia after abdominal surgery and radiation therapy yet was similarly dysphoric (37–39). Although nabilone (Cesamet) has been used successfully in the UK and Canada for over twenty years with no significant drug abuse problems (40), it remains scheduled as a narcotic by the Food and Drug Administration. Currently nabilone, marinol (a synthetic ⁹-THC marketed by Unimed Pharmaceuticals, Buffalo, IL), and Sativex (marijuana plant extract spray marketed by GW Pharmaceuticals, London, UK) are the only approved cannabinoid-based medicines.

More recently, ⁹-THC analogs such as the tricyclic benzopyran HU 210 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahy-dro-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol], the bicyclic CP-55,940 [5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl )cyclohexyl)phenol], and the amino-alkylindole WIN 55,212-2 [(R)(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt], have been characterized as highly potent cannabinoid receptor agonists. The CB₁ and CB₂ receptors show comparable affinity for many cannabinoid agonists, including ⁹-THC, CP-55,940, HU 210, WIN 55,212-2, levonantradol, and nabilone; however, selective agonists and antagonists have been synthesized for both receptors (Table 2), providing useful pharmacological tools that supplement the avail-ability of CB₁, CB₂, and CB₁/CB₂ knockout mice (41–45). These tools will be essential in elucidating the pharmacology and physiology of cannabinoid action and in engineering therapeutic molecules with minimal side effects.

	CANNABINOID RECEPTORS

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

The amino acid sequence of the CB₁ receptor is relatively conserved across several species, including mammals, fish, hydra, mollusk, leech, and sea urchin (48–52), but is not thought to be expressed in insects (53). CB₁ receptors are found predominantly in the presynaptic terminals of the CNS; however, they are also found in lower abundance in the periphery, including the immune system, testis, vascular endothelium, small intestine, liver, and peripheral nerve synapses (54–57). Although CB₁ receptors are found throughout the brain, they are most dense in the cortex, hippocampus, basal ganglia, cerebellum, and spinal cord; this distribution is consistent with the effects of cannabinoids on memory, cognition, movement, and nociception (58, 59).

In contrast to CB₁, the CB₂ receptor is primarily expressed on immune cells in the periphery and acts to modulate immune function (4, 60). CB₂ receptors are also expressed in tonsils, bone marrow, thymus, pancreas, adult rat retina, and peripheral nerve terminals in the mouse vas deferens (61). Particularly high expression levels are found on B cells and natural killer cells. CB₂ signaling is thought to mediate cannabinoid inhibition of T cell proliferation, modulation of proinflammatory cytokine secretion, and B cell responses (62). Although originally thought to be absent in the CNS (4), CB₂ receptor mRNA has been detected in cerebellar granule cells (63) and is upregulated in nervous tissue following inflammatory activation (64, 65). Recent evidence, in fact, shows significant CB₂ receptor expression in the CNS, particularly in regions of the brain stem (66). Many ligands (especially those described earlier in the literature; see Tables 1 and 2) do not distinguish between the CB₁ and CB₂ receptors, despite only 44% overall amino acid sequence identity. This commonality of ligand binding, however, may be explained by the similarity (i.e., 68% identity) of their orthosteric ligand binding domains (4). In any case, selective CB₂ ligands have become an area of active investigation (Table 2).

At the molecular level, both CB₁ and CB₂ receptors predominantly signal through activation of G_i/o proteins thereby resulting in the inhibition of adenylyl cyclase and reducing cAMP levels (67, 68). CB₁ receptor activation is also linked to inhibition of N- and Q-type Ca²⁺ channels; activation of mitogen-activated protein kinases (MAPKs); expression of immediate early genes (e.g., krox-24); and activation of inwardly rectifying K⁺ channels. CB₂ receptors display signaling similar to CB₁ receptors, including MAPK activation; however, in contrast to CB₁ receptors, CB₂ receptor activation has not been shown to affect ion channel function (Table 1) (62, 68).

	ENDOCANNABINOIDS

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
The discovery that the phytocannabinoid ⁹-THC binds to specific receptor proteins to elicit intracellular signaling events was an early indicator of the existence of one or more endogenous compounds that could exert neurotransmitter or hormonal control over central and peripheral CB₁ and CB₂ receptors. Endocannabinoids are now recognized as significant intracellular lipid signaling molecules that act in the central and peripheral nervous systems to regulate physiological, behavioral, and emotional functions. The first endocannabinoid identified, from porcine brain tissue, was anandamide (N-ara-chidonoylethanolamide; i.e., the fatty acid arachidonic acid coupled through an amide bond to ethanolamine) (5). Anandamide was subsequently isolated from human brain (69) and has been shown to mimic cannabinoid agonist activity in vitro (70, 71) and in vivo, capable of eliciting the classical tetrad of ⁹-THC-induced effects (i.e., analgesia, catalepsy, hypothermia, and hypomotility) (72).

Since the discovery of anandamide, a number of fatty acid–containing molecules with full or partial agonist activity at CB₁ and/or CB₂ have been either extracted from native tissues or chemically synthesized. These molecules, however, do not selectively modulate cannabinoid receptor signaling; they affect a variety of proteins, including ion channels (e.g., TRPV1), GPCRs (e.g., serotonin receptors), and enzymes (73, 74). The derivation of lipid messenger molecules from long-chain polyunsaturated fatty acids is reminiscent of the eicosanoid and prostanoid families of bioactive molecules. It is likely that many more lipid mediators will be discovered within the lipidome.

Besides anandamide, the most widely studied endocannabinoids are 2-arachidonoyl glycerol (2-AG) (6), 2-arachidonyl glyceryl ether (noladin ether) (8), and virodhamine (9). Levels of 2-AG in the brain are frequently one or two orders of magnitude higher than anandamide levels, although the physiological relevance of this concentration difference is unclear. Future research is needed to define cannabinoid receptor–specific neurotransmitters in terms of receptor type selectivity, localization of proteins involved in transmitter synthesis and degradation, relevant local concentrations proximal to receptors, and signaling crosstalk with other neurotransmitter systems.

Unlike neurotransmitter molecules that are typically held in vesicles prior to synaptic release, anandamide is synthesized on demand within the plasma membrane. One of the prevailing pathways for synthesis and release of anandamide begins with the transfer of arachidonic acid from the sn-1 position of rare phospholipids to the sn-3 position of phosphatidylethanolamine, thereby creating N-arachidonoyl phosphatidylethanolamine (NAPE). The reaction is catalyzed by a Ca²⁺-dependent N-acyl transferase (NAT) activity. A specific Ca²⁺-dependent enzyme then hydrolyzes NAPE’s phosphodiester bond (11, 14, 16, 75), releasing anandamide into the synapse from either the pre- or postsynaptic plasma membranes (Figure 1) (76–78). Although originally called NAPE-PLD, this enzyme is a member of the zinc metallohydrolase family of enzymes. Alternative synthetic pathways have been hypothesized for anandamide, including sequential release of arachidonic acid and ethanolamine from phosptidylethanolamine through the action of phospholipase A₂ and lysophospholipase D, respectively, and then condensation to anandamide through the action of a synthase-like enzyme (79). It is possible that different tissue- or cell-specific synthetic routes exist for fatty acid amide or glycerol ester endocannabinoids.

View larger version (22K): [in this window] [in a new window]   Figure 1: The Endocannabinoid Synapse NAPE (N-arachidonoylphosphatidyl ethanolamine) is hydrolyzed by NAPE phospholipase D (NAPE-PLD) to release free anandamide (AEA). Alternatively, precursor phospholipids are hydrolyzed by diglyceride lipase and phospholipase C to release the resident fatty acid (FA) from the sn-1 position and phosphatidyl-ethanolamine (p-EA) from the sn-3 position, respectively, yielding 2-arachidonoylglycerol (2-AG). Anandamide and 2-AG are agonists at the CB1 receptor. Anandamide can also be released from postsynaptic terminals to signal in a retrograde fashion to presynaptic CB1 receptors. The CB1 receptor either blocks or stimulates adenylate cyclase (AC) depending on cell type. CB1 receptors block neurotransmitter release from the presynaptic terminal. Disposal of anandamide, to yield EA and arachadonic acid (AA), and 2-AG is via movement across the plasma membrane followed by hydrolysis by cytoplasmic fatty acid amide hydrolase (FAAH). As discussed in the text, this movement of anandamide may involve a protein transporter (blue cylinder) that may work in conjunction with FAAH. 2-AG is also transported across the plasma membrane by a similar process and hydrolyzed by monoacylglyceride lipase.

	ANANDAMIDE UPTAKE AND HYDROLYSIS

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
Termination of anandamide signaling appears to involve a two-step process beginning with transport across the plasma membrane followed by enzymatic hydrolysis into arachidonic acid and ethanolamine by cytoplasmic FAAH (10, 17, 19, 23, 81, 82). Functional anandamide transport activity has been well characterized in several cell types derived from rat, mouse, and human tissues (Table 3). Most cells display a rapid (t_1/2 = 2.5 – 4 min) (21, 83), saturable (K_m = 0.190 – 45 µM), temperature dependent (Q₁₀ = 1.6) (83), and enantioselective (18) mechanism for transport of anandamide; only a minor component of anandamide uptake is nonsaturable and occurs by diffusion. Reversible transport has been demonstrated in cells preloaded with radiolabeled anandamide (17). Evidence from structure–activity studies using anandamide analogs indicates that the transport process in whole cells has narrow structural requirements (18, 84–86), supporting the hypothesis that anandamide uptake occurs via a protein carrier–mediated process. However, pharmacological characterization of the transport process has been hampered by the paucity of selective inhibitors. Inhibitors that are analogs of anandamide, such as AM404 (IC₅₀ = 1 µM) (19), inhibit both anandamide uptake and FAAH activity, suggesting that FAAH and the transport protein share a structurally similar binding site (87–89). Several groups have reported substances that selectively inhibit the cellular uptake of anandamide with no apparent effect on FAAH activity (87–92), but it is not clear whether these compounds truly represent selective inhibitors or merely reflect limited access to cytoplasmic FAAH. A recent publication attempted to provide an assessment of the ability of putative inhibitors to block functional anandamide uptake, FAAH enzyme activity, and transport protein binding and concluded that no selective tools currently exist for either FAAH or transport inhibition (93). Similar conclusions were made by other investigators with a selected group of putative selective inhibitors (94).

	MOLECULAR MODELS OF ANANDAMIDE UPTAKE

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

MODEL 1: PLASMA MEMBRANE–ASSOCIATED FAAH
FAAH appears primarily localized within perinuclear membranes and is not found at the plasma membrane. Immunohistochemical studies of the rat CNS reveal punctate cytoplasmic inclusions of FAAH within the cell bodies and dendrites of pyramidal and Purkinje cells (100, 101), and confocal fluorescence microscopy identifies punctate FAAH immunoreactivity in perinuclear areas (102). More recently, the physical separation of FAAH from the plasma membrane has been taken to suggest that transport is independent of hydrolysis (82). However, these studies cannot rule out an undetected but physiologically relevant level of FAAH at the plasma membrane more proximal, perhaps even adjacent, to the transport protein that would allow for concerted anandamide uptake and hydrolysis (Figure 2).

View larger version (58K): [in this window] [in a new window]   Figure 2. Anandamide Transport by Plasma Membrane-Associated FAAH (Model 1). This model of transport requires fatty acid amide hydrolase (FAAH, red) alone to bind anandamide from the extracellular space directly. The curved black arrow represents FAAH-mediated hydrolysis of anandamide into ethanolamine and arachidonic acid. See text for details.

The crystal structure of FAAH supports the presence of several domains that grant the enzyme access to both the inner leaflet of the plasma membrane and the cytoplasmic milieu (23, 116). The substrate channel is amphipathic, which may allow the admission and movement of the polar head group of anandamide into the active site of FAAH. Another channel is comprised almost entirely of hydrophobic residues thought to be responsible for substrate binding and recognition. A third channel creates a solvent-exposed cytosolic port (116). Following anandamide hydrolysis, liberated fatty acid and amine products can be envisaged to exit the enzyme via the membrane- and cytosolic-access channels, respectively (116). These structural features are consistent with a plasma membrane–associated enzyme that accepts anandamide directly from the extracellular space or through diffusional processes (see below), or possibly through protein-mediated facilitated diffusion as described below. These features are also consistent with perinuclear-localized FAAH, which would receive anandamide through passive diffusion or endocytotic transport (see below).

MODEL 2: PASSIVE DIFFUSION DRIVEN BY FAAH
It has been proposed that anandamide accumulation is solely dependent on passive diffusion across the plasma membrane and that FAAH-mediated enzymatic cleavage of anandamide maintains the inward concentration gradient and drives continued anandamide uptake (102) (Figure 3). In this model, lipophilic anandamide diffuses through the plasma membrane where it eventually integrates into FAAH-enriched perinuclear membranes (82). In concordance with this hypothesis, a specific transport protein has been elusive, and anandamide uptake is not readily inhibited by traditional uptake inhibitors as measured within five to thirty seconds (96, 102). However, measurements of anandamide uptake at short time points may reflect non-specific integration of highly lipophilic anandamide into the cell membrane rather than specific transport. In a recent review, the authors allowed for the possibility that diffusion accounts for the initial non-specific process, which may be followed by a specific uptake process (96). In addition, the recent identification of a binding site involved in anandamide transport has challenged the passive diffusion theory (22); however, a passive diffusion process may be relevant for signaling-independent absorption and recycling of lipid molecules in specific cell types. For example, FAAH-deficient cell types do exist and yet accumulate anandamide, albeit at significantly reduced rates compared to FAAH-expressing cells (117).

View larger version (59K): [in this window] [in a new window]   Figure 3. Passive Diffusion of Anandamide Driven by FAAH (Model 2). In this model, the sole function of FAAH (red) is to establish a concentration gradient of anandamide transport (blue arrow) through hydrolysis of anandamide into arachidonic acid and ethanolamine. FAAH is localized exclusively in the perinuclear area. Delivery of anandamide to perinuclear FAAH may require a special protein or process currently undefined.

View larger version (59K): [in this window] [in a new window]   Figure 4. Endocytosis-Mediated Anandamide Uptake (Model 3). In this model, anandamide enters the cell through the plasma membrane via a rapid endocytotic process (short blue arrows), which may involve ancillary binding proteins (orange), and is delivered to cytoplasmic FAAH (red) for hydrolysis.

View larger version (63K): [in this window] [in a new window]   Figure 5. Facilitative Diffusion of Anandamide (Model 4). This model involves a specific plasma membrane binding protein (orange) that facilitates anandamide transport across the plasma membrane. Although the highest concentration of FAAH (red) has been localized to perinuclear compartments, our working hypothesis suggests that sufficient FAAH resides at the plasma membrane closely associated with the transport protein or moves to the plasma membrane based on use-dependency to facilitate transport and hydrolysis.

ANANDAMIDE AT THE PLASMA MEMBRANE
Recently, translocases have begun to emerge as candidates for the anandamide transporter. Translocases are membrane bound proteins that "flip" aliphatic compounds from one leaflet of the membrane to the other, in a concentration-dependent manner; however, in contrast to the anandamide transporter (17), translocases are generally ATP-dependent. The anandamide transporter may be related to the family of translocases that includes the CD36/FAT protein that translocates arachidonic acid, a major structural component of the anandamide molecule (127).

Due to its amphipathic nature, the conformation of anandamide is an important determinant in its interaction with plasma membrane proteins. A recent study demonstrates that, once inserted into the plasma membrane’s outer leaflet, anandamide adopts an extended conformation, such that its polar ethanolamine head group lines up with the polar head group of the neighboring phospholipid within the membrane and the aliphatic tail points towards the bilayer center (128–130). The results of this study are consistent with the hypothesis that anandamide approaches the CB₁ receptor binding site by fast lateral diffusion within the outer membrane leaflet, where it interacts with the hydrophobic groove formed by helices 3 and 6 of the CB₁ receptor, thus activating the receptor (80, 131, 132). If it is indeed the case that anandamide laterally diffuses in the outer membrane leaflet to activate the CB₁ receptor, then translocation of anandamide to the inner leaflet of the plasma membrane may be the step that serves, independent of hydrolysis per se, to extinguish its biological activity. A translocase similar to FAT/ CD36 would be a logical candidate to perform such a task.

	CONCLUSION

TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 
The endocannabinoid transport process promises to be a useful therapeutic target to leverage cannabinoid receptor agonism with the potential to avoid psychtropic side effects. The question still remains as to how an anandamide transport protein and FAAH might interact in order to orchestrate the metabolism of anandamide. In a recent study, Oddi and coworkers (65) demonstrate that FAAH activity primarily resides in intracellular perinuclear membranes, whereas transport activity is localized almost exclusively in plasma membrane fractions. Immunostaining of live cells has demonstrated that FAAH is primarily localized in intracellular regions (133). The physical separation of these distinct activities compels the question: Does anandamide travel to the perinuclear membrane to meet FAAH, or does FAAH travel to the plasma membrane to meet anandamide? It is also not clear if anandamide diffuses through the cytoplasm, carried by a yet unknown binding protein, or if it is transported via endocytosis. Due to the lipophilic nature of anandamide, it is unlikely that it diffuses unaided through the cytoplasm to the perinuclear membranes, giving strength to an endocytic mechanism. It is also possible that trace levels of FAAH in the plasma membrane are sufficient to drive facilitative diffusion. Perhaps FAAH is stored in perinuclear membranes and translocated to the plasma membrane when stimulated by anandamide-mediated cannabinoid receptor signaling events.

The pending launch of the first bone fide cannabinoid therapeutic agent opens the door to the development of other possible therapeutic agents that may exploit cannabinoid mechanisms. Rimonabant is a CB₁ receptor antagonist being developed for obesity and metabolic syndrome, promising to reduce appetite through dampening of the cravings for highly palliative foods and to positively modify lipid profiles. Cannabinoid receptors are abundant in both the CNS and periphery and fit into the well-heeled GPCR-centric approach to drug development. However, no group has yet achieved selective stimulation of either CB₁ or CB₂ receptors or developed a novel approach to providing cannabinoid receptor agonism while simultaneously avoiding psychotropic side effects. Additional targets are emerging including endocannabinoid reuptake blockade and concomitant augmentation of cannabinoid neurotransmission. Mechanistically, the result of reuptake or hydrolysis blockade should provide the therapeutic benefit of cannabinoid receptor activation in a more physiologically relevant temporal and spatial context. The hope is to avoid undesirable psychotropic and systemic side effects. Although the complexity of endocannabinoid signaling and mechanism of cannabinoid regulation have yet to be fully defined, they clearly warrant further exploration as means of therapeutically exploiting stimulation of the cannabinoid system while avoiding liabilities associated with the use of medicinal marijuana.

Christian Felder, PhD, completed his doctoral work in the Deptartment of Biochemistry at Georgetown University School of Medicine. He completed his postdoctoral training in the laboratory of Julius Axelrod at the NIMH in 1990. As Chief of the Unit on Cell and Molecular Signaling at the NIMH, he continued to work with Julius Axelrod investigating the pharmacology and signal transduction of G protein–coupled receptors with a focus on the muscarinic and cannabinoid receptor families. He is currently a Research Fellow in Neuroscience at Eli Lilly & Co., focusing on the neurobiology of psychiatric diseases.

Amy K. Dickason-Chesterfield, MS, is an Assistant Senior Biologist in the Department of Neuroscience at Eli Lilly & Co. She is also a doctoral student at Miami University working under the guidance of Chris Felder and Phyllis Callahan. She attended Hanover College and Miami University for her undergraduate and graduate studies, respectively.

Steven Moore, PhD, received his doctoral degree from the Department of Cell and Structural Biology at the University of Illinois at Urbana-Champaign in 2003. He completed his postdoctoral training in the laboratory of Christian Felder in the Neuroscience Division of Eli Lilly and Company in 2005, and subsequently joined the R&D department of Pierce Biotechnology in Rockford, Illinois.

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TOP Summary Introduction Cannabinoid Pharmacology Cannabinoid Receptors Endocannabinoids Anandamide Uptake and Hydrolysis Molecular Models of Anandamide... Conclusion References

 

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