Current Drug Targets - Volume 11, Issue 4, 2010

Addiction and Pain: Cannabinoid and Opioid Interactions The goal of this special issue of Current Drug Targets is to report and update our current knowledge in molecular and functional aspects of cannabinoid and opioid interactions in relation to addiction and pain. It has been known for several years that cannabinoids and opioids share several pharmacological actions such as antinociception, sedation, hypothermia and hypotension. However, only recent evidence has suggested that these two systems interact and are involved in many physiological and pathological functions. This cross talk could be a target for intervention in the treatment of pain and addiction. In the current issue several leading investigators report new findings about molecular mechanisms behind this interaction. Additionally, the role of cannabinoid-opioid relationship is reviewed in relationship to pain and drugs of abuse such as nicotine, MDMA and alcohol. Dr. Parolaro and co-workers review focuses on molecular mechanisms underlying central and peripheral interactions. The authors highlight the relevance of receptor co-expression and signal transduction mechanisms. They also suggest that the nature of opioid and cannabinoid interaction could differ between circuits mediating addiction and those mediating other functions such as antinociception, emotion and cognition. The addiction aspect of this issue commences with Dr. Lopez-Moreno and co-workers review of the role of functional interactions between the opioid and endocannabinoid systems in alcohol relapse behavior. They also discuss the link between receptor polymorphism that lead to altered opioid and cannabinoid neurotransmission leading to an increased propensity to drug addiction. MDMA (ecstasy) is an addictive amphetamine derivative with psychostimulant properties. The role of the opioid and endocannabinoid system as a modulator of the rewarding/reinforcing properties of MDMA is reviewed by Dr. Robledo. Dr. Maldonado and Dr. Berrendero review recent behavioural and biochemical data on the role of cannabinoid and opioid neurotransmission in the different processes linked to nicotine addiction. They conclude their review by suggesting pharmacological manipulations as a potential therapeutical strategy for treating nicotine and perhaps addiction to other drugs of abuse. Based on the knowledge that that maternal exposure to drugs alters brain circuits, Dr. Spano and co-workers examined molecular and behavioural consequences of maternal exposure to opioids and cannabinoids. They also reviewed the impact of long term exposure at different developmental stages concluding that at least in pre-clinical studies exposure to both cannabinoids and opioids at early developmental stages predicts greater likelihood of intake in adulthood. The issue finalises with Dr. Desroches and Dr. Beaulieu review which focuses on cannabinoid and opioid interactions in pain modulation. They highlight potential of additive or even synergistic antinociceptive effects of both neurotransmitter systems, emphasising their clinical relevance. I would like to thank all the contributors of this special issue for their time, experience, and insights to these important topics.

Recently, the presence of functional interaction between the opioid and cannabinoid system has been shown in various pharmacological responses. Although there is an increasing interest for the feasible therapeutic application of a co-administration of cannabinoids and opioids in some disorders (i.e. to manage pain, to modulate immune system and emotions) and the combined use of the two drugs by drug abusers is becoming largely diffuse, only few papers focused on cellular and molecular mechanisms underlying this interaction. This review updates the biochemical and molecular underpinnings of opioid and cannabinoid interaction, both within the central nervous system and periphery. The most convincing theory for the explanation of this reciprocal interaction involves (i) the release of opioid peptides by cannabinoids or endocannabinoids by opioids, (ii) the existence of a direct receptor-receptor interaction when the receptors are co-expressed in the same cells, and (iii) the interaction of their intracellular pathways. Finally, the cannabinoid/opioid interaction might be different in the brain rewarding networks and in those accounting for other pharmacological effects (antinociception, modulation of emotionality and cognitive behavior), as well as between the central nervous system and periphery. Further insights about the cannabinoid/opioid interaction could pave the way for new and promising therapeutic approaches.

Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.

3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine derivative with psychostimulant properties. This substance is widely used around the world by young adults in recreational settings. One of the most remarkable characteristics of ecstasy users is the concurrent consumption of several other drugs of abuse including psychostimulants, alcohol, tobacco, LSD, cannabis, and opioids. This poly-drug pattern of use is now prompting research towards understanding how the combination of MDMA with cannabis and opioids could affect neuropsychobiological processes related to addiction. As with other drugs of abuse, behavioural evidence has been presented supporting the role of the endocannabinoid system as a modulator of the rewarding/reinforcing properties of MDMA. On the other hand, the neurochemical substrate for the complex interactions between the endocannabinoid system and MDMA is poorly understood. MDMA also modulates the activity of the dynorphinergic and enkephalinergic systems in several brain structures related to addiction, as it has been shown for other psychostimulants. The work regarding the contribution of μ- and δ-opioid receptors in the rewarding effects of MDMA shows differential results in pharmacological studies in rats, with respect to studies using knock-out mice. The present review describes the behavioural and neurochemical interactions between MDMA, cannabinoids, and opioids with respect to addiction processes.

Nicotine addiction is a complex behavioural alteration, in which many neuronal pathways and neurotransmitters are involved. For a long time, dopamine has been considered one of the most important neurotransmitters in mediating the rewarding effects of nicotine. In addition, a great amount of research suggests that the endogenous cannabinoid and opioid systems play an overall modulatory effect on the reward circuitry and participate in the addictive properties of most of the prototypical drugs of abuse. This review focuses on recent behavioural and biochemical data involving these systems in the different processes that contribute to tobacco addiction. A possible role for the endogenous cannabinoid and opioid systems in the rewarding properties of nicotine as well as in the development of nicotine physical dependence and relapse to nicotine-seeking behaviour will be examined. According to preclinical studies, clinical trials suggest that the manipulation of these systems with cannabinoid or opioid antagonists could be a potential therapeutical strategy for treating nicotine addiction.

Cannabinoids and opioids are known to strictly interact in many physiological and pathological functions, including addiction. The endogenous opioid system is significantly influenced by maternal or perinatal cannabinoid exposure, major changes concerning operant behaviour in adult animals. Copious data suggests that adolescence is also a particularly sensitive period of life not only for the initiation of abusing illicit drugs, but also for the effects that these drugs exert on the neural circuitries leading to drug dependence. This paper examines the role played by the age of drug exposure in the susceptibility to discriminative and reinforcing effects of both cannabinoids and opioids. We first revisited evidence of alterations in the density and functionality of mu-opioid and CB1 cannabinoid receptors in reward-related brain regions caused by either maternal, postnatal, adolescent or adult exposure to opioids and cannabinoids. Then, we reviewed behavioural evidence of the long-term consequences of exposure to opioids and cannabinoids during gestation, postnatal period, adolescence or adulthood, focusing mostly on drug discrimination and self-administration studies. Overall, evidence confirms a neurobiological convergence of the cannabinoid and opioid systems that is manifest at both receptor and behavioural levels. Although discrepant results have been reported, some data support the gateway hypothesis that adolescent cannabis exposure contributes to greater opioid intake in adulthood. However, it should be kept into consideration that in humans genetic, environmental, and social factors could influence the direct neurobiological effects of early cannabis exposure to the progression to adult drug abuse.

Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. Indeed, it is widely known that activation of either opioid or cannabinoid systems produces antinociceptive properties in different pain models. Moreover, several biochemical, molecular and pharmacological studies support the existence of reciprocal interactions between both systems, suggesting a common underlying mechanism. Further studies have demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception. These interactions may lead to additive or even synergistic antinociceptive effects, emphasizing their clinical relevance in humans in order to enhance analgesic effects with lower doses and consequently fewer undesirable side effects. Thus, the present review is focused on bidirectional interactions between opioids and cannabinoids and their potent repercussions on pain modulation.

Epithelial ovarian cancer is the leading cause of death for gynecological cancer in most of the Western world; lethality ensues from the occurrence of occult metastasis within the peritoneal cavity, a process requiring the acquisition of capacity for migration and invasiveness by ovarian tumor cells (metastatic phenotype), and characterized by a complex series of interrelated cellular events. Unlike most carcinomas that dedifferentiate during neoplastic progression with loss of epithelial E-cadherin (epithelial to mesenchymal transition, EMT), ovarian carcinomas undergo transition to a more epithelial phenotype, early in tumor progression, with increased E-cadherin expression. Subsequent reacquisition of mesenchymal features is observed in late-stage tumors, and loss of E-cadherin expression or function is a factor in ovarian cancer progression. Changes in E-cadherin expression are indicative of the phenotypic plasticity that occurs in ovarian cancer, with a variety of signal transduction pathways impinging on the regulation of E-cadherin levels or subcellular distribution. Among them, the Snail transcription family, consisting of members SNAIL and SLUG, is thought to be mainly involved in the repression of E-cadherin expression, leading to EMT. E-cadherin, SNAIL, and SLUG also represent crucial targets of estrogen signaling. In this review, we discuss recent advances in the understanding of the role of estrogen signaling in the complex network underlying the phenotypic plasticity in ovarian cancer. Insight into the mechanisms involved will allow rational drug designs, aimed at the molecules critical to cellular signaling.

T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T-cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line.

It has been well recognized that inflammatory responses are part of pathogenesis for various disorders such as autoimmune diseases. For example, multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system that is presumably caused by activated T cells specific for myelin antigens. Rheumatoid arthritis (RA) is also a chronic inflammatory disease characterized by synovial inflammation in which several inflammatory cytokines are involved. On the other hand, Osteopontin (Opn) is a pleiotropic cytokine expressed by activated T cells, dendritic cells (DCs) and macrophages and its expression is up-regulated during inflammation. Secreted form of Opn (s-Opn), which is modified by phosphorylation, glycosylation and proteolytic cleavage with thrombin, has activities as a T helper type 1 (Th1) cytokine and as a chemoattractant for many types of cells through integrin receptors and CD44. Recently, it has been uncovered that intracellular form of Opn (i-Opn) is a critical regulator for Toll like receptor-9 (TLR-9), TLR-7- dependent interferon-α (IFN-α) expression by plasmacytoid DCs and Th17 development. In this review, we have summarized recent progress in understanding of Opn's role in variety of inflammatory disorders.

γ-secretase is an intramembranous multi-protein complex that cleaves many type-I proteins with critical roles in neuronal function. In Alzheimer's disease (AD) interest in γ-secretase comes, in part, from the fact that this complex is responsible for the last cleavage step of the amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ). Aβ represents the primary component of the amyloid plaque, one of the main pathological hallmarks of AD. Over the last years, considerable efforts have been made to develop drugs to reduce Aβ production with the aim to slow AD progression. Many inhibitors of this protease have been identified, although the clinical use has been limited by concerns about the possible toxicity of these compounds. γ-secretase inhibitors have been shown to reduce Aβ in vitro and in vivo, but interference with Notch proteolysis causes immunological and gastrointestinal toxicity in animal models. The observation that some nonsteroidal anti-inflammatory drug (NSAID) derivatives are able to specifically lower Aβ42 and the development of inhibitors with Notch-sparing selectivity has revived the interest in γ-secretase as an attractive target for drug intervention in AD. Despite the fact that all clinical trials with NSAIDs or γ-secretase modulators in AD have failed to show clinical benefit thus far, the main concern is that the Aβ-lowering potency of the tested compounds may be too low. Active efforts are being made to develop compounds able to penetrate into the brain to lower Aβ at physiological doses without interfering with the cleavage and function of other critical γ-secretase substrates. These novel inhibitors and modulators may soon offer hope in the Alzheimer's fight.