Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight

The endocannabinoid system consists of lipid-derived agonists that activate cannabinoid (CB) receptors. CB receptor agonists, namely, the phytocannabinoid Δ(9)-THC and the endocannabinoid anandamide, increase hunger sensation and food intake. These discoveries led to the clinical use of Δ(9)-THC derivatives for the treatment of cancer and HIV-related nausea and cachexia. Animal studies clarified the important role of CB1 receptors in the hypothalamus and in the limbic system in mediating orexigenic effects. In parallel, data on CB1-specific blockade either by drugs or by genetic ablation further demonstrated that CB1 inhibition protects against weight gain induced by high-fat feeding and reduces body weight in obese animals and humans. The mechanisms of weight reduction by CB1 blockade are complex: they comprise interactions with several orexigenic and anorexigenic neuropeptides and hormones, regulation of sympathetic activity, influences on mitochondrial function, and on lipogenesis. Although these mechanisms appear to be mainly mediated by the CNS, weight loss also occurs when drugs that do not reach CNS concentrations sufficient to inhibit CB1 signaling are used. The development of peripherally restricted CB1 inverse agonists and antagonists opened new routes in CB1 pharmacology because centrally acting CB1 inverse agonists, e.g., rimonabant and taranabant, exerted unacceptable side effects that precluded their further development and application as weight loss drugs. Tissue and circulating endocannabinoid concentrations are often increased in animal models of obesity and in obese humans, especially those with visceral fat accumulation. Thus, further research on CB1 inhibition is still promising to treat human obesity.     

Therapeutic potential of targeting the endocannabinoids: implications for the treatment of obesity, metabolic syndrome, drug abuse and smoking cessation

Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.     

Cannabinoid receptor ligands: clinical and neuropharmacological considerations,relevant to future drug discovery and development

This review highlights some important advances that have taken place in cannabinoid research over the last four years. It focuses on novel ligands that are of interest either as experimental tools or as lead compounds for therapeutic agents and possible clinical applications for some of these ligands. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that together constitute the 'endocannabinoid system'. These are CB1 cannabinoid receptors that are present mainly on central and peripheral neurones, CB2 cannabinoid receptors that are expressed predominantly by immune cells, the biochemical mechanisms responsible for the tissue uptake or metabolism of endocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonists for CB1 and CB2 receptors, a potent CB2-selective antagonist/inverse agonist and inhibitors of endocannabinoid uptake or metabolism. Future research should be directed at characterising the endocannabinoid system more completely and at obtaining more conclusive clinical data about the possible beneficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB1/CB2 receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB1 receptor activation are now emerging and these are discussed at the end of this review.     

Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk

Introduction: Obesity and related cardiometabolic derangements are spiraling global health problems urgently in need of safe, effective and durable pharmacotherapy. Areas covered: As an orexigenic and anabolic biosignaling network, the endocannabinoid system interacts with other information-transducing pathways to help ensure metabolic homeostasis. Hyperphagia stimulates reinforcing neuronal circuits favoring energy intake and conservation, inviting overweight/obesity and cardiometabolic risk factors ('metabolic syndrome'). Associated increases in cannabinoid 1 G protein-coupled receptor (CB1R) activity/expression further exacerbate food consumption and the metabolic shift toward fat production and accumulation. The role of CB1R activity in hyperphagia and weight gain spurred the development of rimonabant (SR141716; Acomplia), the first-in-class CB1R antagonist/inverse agonist weight-loss drug. Rimonabant and similar CB1R inverse agonists also exert pleiotropic actions in addition to weight-loss effects that help correct obesity-related metabolic derangements and reduce cardiovascular risk in humans. The medicinal utility of these agents was crippled by clinically significant central and peripheral adverse effects that appear to reflect CB1R inverse agonists as a class. Consequently, increased attention is being given to CB1R neutral antagonists, CB1R blockers with intrinsically weak, if any, functional potency to elicit the negative-efficacy responses associated with inverse agonists. Laboratory studies demonstrate that CB1R neutral antagonists - whether readily accessible to the central nervous system or not (i.e., 'periphero-neutral' antagonists) - retain the salient therapeutic effects of CB1R inverse agonists on hyperphagia, weight-gain, and obesity-driven metabolic abnormalities with the distinct advantage of being associated with significantly less preclinical adverse events than are conventional CB1R inverse agonists such as rimonabant. Expert opinion: CB1R (periphero-)neutral antagonists merit continued analysis of their molecular pharmacology and evaluation of their therapeutic significance and translational potential as new-generation medicines for obesity-related derangements, including nonalcoholic fatty liver disease and type 2 diabetes, if not obesity itself.     

Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders

Introduction: Excessive abdominal obesity along with other risk factors results in the metabolic syndrome, which can lead to heart disease, Type-2 diabetes, and death. The endocannabinoid system (ECS) is composed of neutral lipids which signal through the G-protein coupled cannabinoid receptors CB1 and CB2. In abdominal obesity, the ECS is generally up-regulated in central and peripheral tissues and its blockade results in positive metabolic changes. Rimonabant (SR141716) was the first selective CB1 inverse agonist/antagonist marketed for the treatment of obesity; however, psychiatric side effects, which may result from its actions in the brain or its inverse agonism, resulted in its removal from the market. Recently, key metabolic-modulatory roles for the ECS within peripheral tissues have come to light. Thus there has been significant effort put forth by several laboratories to develop either neutral or peripherally restricted CB1 antagonists. Areas covered: In this review we shall provide an overview of the roles the ECS plays outside the brain in regulating metabolism, and highlight the latest advances in the development of neutral and/or peripherally restricted CB1 antagonists, and other state of the art strategies that minimize endocannabinoid overactivity. Expert opinion: The CB1 receptor is potentially a clinically relevant target for the design of therapies against metabolic syndrome, deserving the development and clinical testing of CB1-neutral antagonists which can pass the blood - brain barrier or of peripherally restricted inverse agonists/neutral antagonists. Furthermore, reducing endocannabinoid biosynthesis could represent an alternative strategy to counteract peripheral endocannabinoid overactivity through dietary n-3 polyunsaturated fatty acids or the development of diacylglycerol lipase inhibitors.     

Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders

Introduction: Excessive abdominal obesity along with other risk factors results in the metabolic syndrome, which can lead to heart disease, Type-2 diabetes, and death. The endocannabinoid system (ECS) is composed of neutral lipids which signal through the G-protein coupled cannabinoid receptors CB1 and CB2. In abdominal obesity, the ECS is generally up-regulated in central and peripheral tissues and its blockade results in positive metabolic changes. Rimonabant (SR141716) was the first selective CB1 inverse agonist/antagonist marketed for the treatment of obesity; however, psychiatric side effects, which may result from its actions in the brain or its inverse agonism, resulted in its removal from the market. Recently, key metabolic-modulatory roles for the ECS within peripheral tissues have come to light. Thus there has been significant effort put forth by several laboratories to develop either neutral or peripherally restricted CB1 antagonists.

Areas covered: In this review we shall provide an overview of the roles the ECS plays outside the brain in regulating metabolism, and highlight the latest advances in the development of neutral and/or peripherally restricted CB1 antagonists, and other state of the art strategies that minimize endocannabinoid overactivity.

Expert opinion: The CB1 receptor is potentially a clinically relevant target for the design of therapies against metabolic syndrome, deserving the development and clinical testing of CB1-neutral antagonists which can pass the blood – brain barrier or of peripherally restricted inverse agonists/neutral antagonists. Furthermore, reducing endocannabinoid biosynthesis could represent an alternative strategy to counteract peripheral endocannabinoid overactivity through dietary n-3 polyunsaturated fatty acids or the development of diacylglycerol lipase inhibitors.     

Regulation of nausea and vomiting by cannabinoids

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB(1) agonism suppresses vomiting, which is reversed by CB(1) antagonism, and CB(1) inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ(9) -THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB(1) receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT(1A) receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.     

The endocannabinoid system, eating behavior and energy homeostasis: The end or a new beginning?

The endocannabinoid system (ECS) consists of two receptors (CB₁ and CB₂), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB₁ receptor in a feed-forward dysfunction. Several CB₁ antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB₁ ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB₁ partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.     

Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB(1) in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLalpha and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects. Alternatives to systemic blockade include CB(1) partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.     

Pharmacological and molecular characterization of a dorsal root ganglion cell line expressing cannabinoid CB(1) and CB(2) receptors

The behavioral effects evoked by cannabinoids are primarily mediated by the CB(1) and CB(2) cannabinoid receptor subtypes. In vitro pharmacology of cannabinoid receptors has been elucidated using recombinant expression systems expressing either CB(1) or CB(2) receptors, with limited characterization in native cell lines endogenously expressing both CB(1) and CB(2) receptors. In the current study, we report the molecular and pharmacological characterization of the F-11 cell line, a hybridoma of rat dorsal root ganglion neurons and mouse neuroblastoma (N18TG2) cells, reported to endogenously express both cannabinoid receptors. The present study revealed that both receptors are of mouse origin in F-11 cells, and describes the relative gene expression levels between the two receptors. Pharmacological characterization of the F-11 cell line using cannabinoid agonists and antagonists indicated that the functional responses to these cannabinoid ligands are mainly mediated by CB(1) receptors. The non-selective cannabinoid ligands CP 55,940 and WIN 55212-2 are potent agonists and their efficacies in adenylate cyclase and MAPK assays are inhibited by the CB(1) selective antagonist SR141716A (SR1), but not by the CB(2) selective antagonist SR144528 (SR2). The endocannabinoid ligand 2AG, although not active in adenylate cyclase assays, was a potent activator of MAPK signaling in F-11 cells. The analysis of CB(1) and CB(2) receptor gene expression and the characterization of cannabinoid receptor pharmacology in the F-11 cell line demonstrate that it can be used as a tool for interrogating the endogenous signal transduction of cannabinoid receptor subtypes.     

Anti-emetics in development

Despite important advances in pharmacotherapeutic options for the prevention and treatment of nausea and vomiting during the 1990s, a significant proportion of patients still suffer debilitating nausea and vomiting symptoms. The most problematic areas are chemotherapy-induced nausea and vomiting particularly delayed emesis, postoperative nausea and vomiting, opioid-induced nausea and vomiting and motion sickness. The most vigorous research into new anti-emetics has focused on the neurokinin-1 (substance P) antagonists. Clinical trials conducted to date indicate that these agents have similar efficacy to 5-HT₃ antagonists in acute chemotherapy-induced nausea and vomiting, superior efficacy to available agents in delayed emesis, possibly superior efficacy against emesis in postoperative nausea and vomiting and no evidence of efficacy versus opioid or motion-induced nausea and vomiting. Other pharmacological strategies in development include agonising CB1 (cannabinoid) receptors, "broad spectrum" receptor antagonists and H-5T_1A receptor agonists, although clinical trials of these types of agents are not yet available. The neurokinin-1 antagonists appear to be promising agents for some nausea and vomiting states, although further clarification of their role is required.     

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists

INTRODUCTION: Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile. AREAS COVERED: This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication. EXPERT OPINION: The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.     

Pharmacology of cannabinoid receptor ligands.

Mammalian tissues contain at least two types of cannabinoid receptor, CB1 and CB2, both coupled to G proteins. CB1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this endogenous cannabinoid system has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [35S]GTPgammaS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such inverse cannabimimetic effects are inverse agonists rather than pure antagonists is discussed.     

The endocannabinoid system in Huntington's disease

The hypokinetic profile of certain cannabinoid agonists becomes these compounds as promising medicines to attenuate the hyperkinesia that characterizes the first grades of Huntington's disease (HD) and that represents the major neurological abnormality in this disease. The fact that CB(1) receptors, the receptor type involved in motor effects of cannabinoid agonists, are significantly reduced in the basal ganglia during the progression of HD represents a convincing explanation for the hyperkinesia typical of this disorder and supports the usefulness of enhancing CB(1) receptor signaling in HD. However, further studies revealed that the key property that enables certain cannabinoid agonists to reduce hyperkinesia is their capability to directly activate vanilloid TRPV(1) receptors. Cannabinoids may also serve to delay/arrest the progression of HD by protecting striatal projection neurons from death. Several cannabinoid agonists have been tested for this purpose in various animal models of HD, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection are three: (i) a reduction in inflammatory events exerted through activating CB(2) receptors located in glial cells; (ii) a normalization of glutamate homeostasis, then limiting excitotoxicity, an effect that would be exerted through CB(1) receptors; and (iii) an antioxidant effect exerted by cannabinoid receptor-independent mechanisms. The changes experienced by the endocannabinoid signaling system during the striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses proved by CB(2) receptors in glial cells recruited at lesioned sites. The present article will review the neurochemical and pharmacological bases that sustain the importance of the endocannabinoid system in the pathophysiology of HD, trying to collect the present information and the future lines for research on the therapeutic potential of this system in this disorder.     

Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders

Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.     

Targeting the endocannabinoid system in diabesity: Fact or fiction?

‘Diabesity’ refers to a rising epidemic indicated by the intricate relationship between obesity and diabetes. The global prevalence of these coexisting, insidious diseases increases social and economic health burdens at a rapid pace. Numerous reports delineate the involvement of the underlying endocannabinoid (EC) signaling system through the cannabinoid-1 (CB1) receptor in the regulation of metabolism and adiposity. Conversely, EC inverse agonists can result in severe depression and suicidal thoughts through interactions with CB1/2 receptors in the brain. This review attempts to elucidate a possible mechanism for the amelioration of diabesity. Moreover, we also highlight the available targets of the CB1 receptor, which could pave the way for safe and effective therapy.     

Anti-emetics in development

Despite important advances in pharmacotherapeutic options for the prevention and treatment of nausea and vomiting during the 1990s, a significant proportion of patients still suffer debilitating nausea and vomiting symptoms. The most problematic areas are chemotherapy-induced nausea and vomiting particularly delayed emesis, postoperative nausea and vomiting, opioid-induced nausea and vomiting and motion sickness. The most vigorous research into new anti-emetics has focused on the neurokinin-1 (substance P) antagonists. Clinical trials conducted to date indicate that these agents have similar efficacy to 5-HT(3) antagonists in acute chemotherapy-induced nausea and vomiting, superior efficacy to available agents in delayed emesis, possibly superior efficacy against emesis in postoperative nausea and vomiting and no evidence of efficacy versus opioid or motion-induced nausea and vomiting. Other pharmacological strategies in development include agonising CB1 (cannabinoid) receptors, "broad spectrum" receptor antagonists and 5-HT(1A) receptor agonists, although clinical trials of these types of agents are not yet available. The neurokinin-1 antagonists appear to be promising agents for some nausea and vomiting states, although further clarification of their role is required.     

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists

Introduction : Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile.

Areas covered : This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication.

Expert opinion : The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.     

Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development

This review highlights some important advances that have taken place in cannabinoid research over the last four years. It focuses on novel ligands that are of interest either as experimental tools or as lead compounds for therapeutic agents and possible clinical applications for some of these ligands. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that together constitute the 'endocannabinoid system'. These are CB(1) cannabinoid receptors that are present mainly on central and peripheral neurones, CB(2) cannabinoid receptors that are expressed predominantly by immune cells, the biochemical mechanisms responsible for the tissue uptake or metabolism of endocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonists for CB(1) and CB(2) receptors, a potent CB(2)-selective antagonist/inverse agonist and inhibitors of endocannabinoid uptake or metabolism. Future research should be directed at characterising the endocannabinoid system more completely and at obtaining more conclusive clinical data about the possible beneficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB(1)/CB(2) receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB(1) receptor activation are now emerging and these are discussed at the end of this review.     

Pharmacological actions of cannabinoids

Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous ligands for these receptors (endocannabinoids) also exist. These are all eicosanoids; prominent examples include arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol. These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. Cannabinoid receptor antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. Neutral cannabinoid receptor antagonists that seem to lack inverse agonist properties have recently also been developed. As well as acting on CB1 and CB2 receptors, there is convincing evidence that anandamide can activate transient receptor potential vanilloid type 1 (TRPV1) receptors. Certain cannabinoids also appear to have non-CB1, non-CB2, non-TRPV1 targets, for example CB2-like receptors that can mediate antinociception and "abnormal-cannabidiol" receptors that mediate vasorelaxation and promote microglial cell migration. There is evidence too for TRPV1-like receptors on glutamatergic neurons, for alpha2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals, for novel G protein-coupled receptors for R-(+)-WIN55212 and anandamide in the brain and spinal cord, for novel receptors for delta9-tetrahydrocannabinol and cannabinol on perivascular sensory nerves and for novel anandamide receptors in the gastro-intestinal tract. The presence of allosteric sites for cannabinoids on various ion channels and non-cannabinoid receptors has also been proposed. In addition, more information is beginning to emerge about the pharmacological actions of the non-psychoactive plant cannabinoid, cannabidiol. These recent advances in cannabinoid pharmacology are all discussed in this review.