Pharmacological and biochemical interactions between opioids and cannabinoids.

Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans. A number of studies have shown that both types of drugs share several pharmacological properties, including hypothermia, sedation, hypotension, inhibition of both intestinal motility and locomotor activity and, in particular, antinociception. Moreover, phenomena of cross-tolerance or mutual potentiation of some of these pharmacological effects have been reported. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of pharmacological interactions between opioids and cannabinoids, focusing on two aspects: antinociception and drug addiction. The potential biochemical mechanisms involved in these pharmacological interactions are also discussed together with possible therapeutic implications of opioid-cannabinoid interactions.     

Cannabinoids: reward,dependence, and underlying neurochemical mechanisms—a review of recent preclinical data

Background and rationale Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, ⁹-tetrahydrocannabinol (THC).Objectives The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids.Results and conclusions Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability.     

Molecular and cellular basis of cannabinoid and opioid interactions

Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia and stimulation of brain circuitry that are believed to underlie drug addiction and reward. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of biochemical and molecular mechanisms underlying opioid and cannabinoid interaction. Several hypothesis have been formulated to explain this cross-modulation including the release of opioid peptides by cannabinoids or endocannabinoids by opioids and interaction at the level of receptor and/or their signal transduction mechanisms. Moreover it is important to consider that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception. While in vitro studies point to the presence of interaction at various steps along the signal transduction pathway, studies in intact animals are frequently contradictory pending on the used species and the adopted protocol. The presence of reciprocal alteration in receptor density and efficiency as well as the modification in opioid/cannabinoid endogenous systems often do not reflect the behavioral results. Further studies are needed since a better knowledge of the opioid-cannabinoid interaction may lead to exciting therapeutic possibilities.     

A neuropeptide-centric view of psychostimulant addiction

Drugs of abuse all share common properties classically observed in human beings and laboratory animals. They enhance neural firing and dopamine tone within the nucleus accumbens and produce progressively greater drug-induced motor responses defined as behavioural sensitization. They produce conditioned place preference, a behavioural model of incentive motivation, which highlights the role of environmental cues in drug addiction. They increase brain reward function as seen by a lowering of intracranial self-stimulation thresholds. And last but not least, they are self-administered, and sometimes even abused, and can trigger reinstatement of drug-seeking behaviour in animals extinguished from drug self-administration. It has long been considered that the reinforcing properties of virtually all drugs of abuse, more specifically psychostimulants, are primarily dependent on activation of the mesolimbic dopamine system. However, recent evidence raises the importance of dopamine-independent mechanisms in reward-related behaviours. The overwhelming body of evidence that indicates a critical role for the mesolimbic dopamine system in the reinforcing effect of psychostimulants should not mask the key contribution of other modulatory systems in the brain. This review summarizes the complex and subtle role of several neuropeptidergic systems in various aspects of addictive behaviours observed in laboratory animals exposed to psychostimulants. A special emphasis is given to the cannabinoid, opioid, nociceptin/orphanin FQ, corticotropin-releasing factor and hypocretin/orexin systems. The relevance of these systems viewed as potential therapeutic targets for drug addiction is discussed in the light of their narrow pharmacological profile and their effectiveness in preventing drug addiction at doses usually not accompanied by severe side effects.     

Endocannabinoids and drug dependence

Drug dependence is a chronically relapsing disorder, manifested as an intense desire for the drug, with impaired ability to control the urges to take the drug, even at the expense of serious adverse consequences. These behavioral abnormalities develop gradually during repeated exposure to a drug of abuse, and can persist for months or years after discontinuation of use, suggesting that this addiction can be considered a form of drug-induced neural plasticity. Many neurotransmitters, including gamma-aminobutyric acid (GABA), glutamate, acetylcholine, dopamine, serotonin and endogenous opioid peptides, have been implicated in the effects of the various drugs of abuse. Dopamine has been consistently associated with the reinforcing effects of most of them. There is, in addition, a growing body of evidence that the endogenous cannabinoid system might participate in the motivational and dopamine-releasing effects of several drugs of abuse. This review will discuss the latest advances on the mechanisms of cannabinoid dependence and the possible role of the endocannabinoid system in the treatment of addiction, not only to marijuana but also to the other common illicit drugs.     

Modulation of the endocannabinoid system: therapeutic potential against cocaine dependence.

Dependence on cocaine is still a main unresolved medical and social concern, and in spite of research efforts, no pharmacological therapy against cocaine dependence is yet available. Recent studies have shown that the endocannabinoid system participates in specific stages and aspects of drug dependence in general, and some of this evidence suggests an involvement of the cannabinoid system in cocaine effects. For example, cocaine administration has been shown to alter brain endocannabinoid levels, and the endocannabinoid system has been involved in long-term modifications of brain processes that might play a role in neuro/behavioral effects of psychostimulant drugs like cocaine. Human studies show that marijuana dependence is frequently associated with cocaine dependence, and that the cannabinoid receptor CNR1 gene polymorphism might be related to cocaine addiction. This article will review the main papers in the field showing how a modulation of different components of the cannabinoid system might interact with some of the neurobiological/behavioral effects of cocaine related to its reinforcing effects, evaluated in preclinical models or in clinical settings. The goal of this review will be to provide insights into the complex picture of cocaine abuse and addiction, and to extrapolate from such endocannabinoid-cocaine interactions useful information to test the therapeutic potential of cannabinoid ligands and endocannabinoid-level enhancers against cocaine dependence for future preclinical/clinical trials.     

Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses

Several anatomical, biochemical and pharmacological evidence support the existence of bidirectional interactions between cannabinoid and opioid systems. The present review is focused on the participation of the endogenous opioid system in the antinociceptive and emotional-like responses induced by cannabinoids, and the development of tolerance to cannabinoid pharmacological effects. Cannabinoid and opioid agonists produce antinociception by acting on similar structures within the central nervous system, and a peripheral mechanism has been also proposed for both compounds. Pharmacological studies have suggested that the endogenous opioid system could be involved in cannabinoid antinociception and the development of cannabinoid tolerance. Recent studies using knockout mice have also demonstrated the role of the opioid system in cannabinoid antinociception and tolerance, although some discrepancies with the previous pharmacological results have been reported when using knockout mice. On the other hand, cannabinoid administration can induce anxiolytic-like responses that are mediated at least in part by an endogenous opioid activity on micro- and delta-opioid receptors.     

Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. To date, three lines of CB1 knockout mice have been established independently in different laboratories. This chapter reviews the main results obtained with these lines of CB1 knockout mice in several physiological responses that have been previously related to the activity of the endocannabinoid system. Studies using CB1 knockout mice have demonstrated that this receptor participates in the control of several behavioural responses including locomotion, anxiety- and depressive-like states, cognitive functions such as memory and learning processes, cardiovascular responses and feeding. Furthermore, the CB1 cannabinoid receptor is involved in the control of pain by acting at peripheral, spinal and supraspinal levels. The involvement of the CB1 cannabinoid receptor in the behavioural and biochemical processes underlying drug addiction has also been investigated. These CB1 knockouts have provided new findings to clarify the interactions between cannabinoids and the other drugs of abuse such as opioids, psychostimulants, nicotine and ethanol. Recent studies have demonstrated that endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitters, including opioids, gamma-aminobutyric acid (GABA), and cholecystokinin (CCK), which could explain some of the responses observed after the stimulation of the CB1 cannabinoid receptor. This review provides an update of the apparently controversial data reported in the literature using the three different lines of CB1 knockout mice, which seem to be mainly due to the use of different experimental procedures rather than any constitutive alteration in these lines of knockouts.     

Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization.

The endogenous cannabinoid system is a relatively novel discovered system consisting of cannabinoid CB1 receptors, which are expressed both in the periphery and in the central nervous system, peripheral cannabinoid CB2 receptors and endogenous cannabinoids, which are anandamide and 2-arachidonyl glycerol. The cannabinoid CB1 receptors have recently been implicated in rewarding aspects of not only the cannabinoid drug Delta9-tetrahydrocannabinol (Delta9-THC), but also of other drugs of abuse, including cocaine. The present study was designed to further investigate the role of CB1 receptors in reward-related effects of cocaine. Using the CB1 receptor selective antagonist SR141716A, the involvement of CB1 receptors in cocaine reinforcement was determined by intravenous cocaine self-administration. In addition, the effects of the CB1 receptor selective antagonist SR141716A upon the development of cocaine-induced behavioural sensitization were investigated. SR141716A did not affect cocaine reinforcement nor did it affect the development of behavioural sensitization to the locomotor stimulant effects of cocaine. These findings suggest that CB1 receptors are not involved in acute cocaine reinforcement nor in cocaine-induced behavioural sensitization.     

Cannabinoid tolerance and dependence: a review of studies in laboratory animals

Two are the issues on cannabis addiction that provoke more controversy from a research perspective. The first one is related to the development of tolerance phenomena and, in particular, of a dependence state after chronic cannabinoid consumption, with appearance of withdrawal signs when this is interrupted, that would be (or not) comparable to those observed for other drugs. A second controversial issue is related to the possibility that chronic cannabinoid consumption may increase the risk to consume other drugs of greater addictive power. Since the discovery in the 1990s of the endocannabinoid signaling system as the target for the action of plant-derived cannabinoids, many studies have addressed these two questions in laboratory animals and, although the results have resulted controversial in various aspects, the following conclusions seem evident: (i) prolonged exposure to plant-derived, synthetic or endogenous cannabinoid agonists in laboratory animals is currently associated with the development of tolerance for most of their pharmacological effects, (ii) tolerance is essentially due to adaptative phenomena consisting in pharmacodynamic events (down-regulation/desensitization of cannabinoid receptors), although some evidence exist on additional pharmacokinetic responses, (iii) the discontinuation of chronic cannabinoid treatment does not elicit abstinence responses spontaneously in most of the cases, presumably because the pharmacokinetic characteristics of cannabinoids, but these responses may be elicited after the blockade of cannabinoid CB1 receptors in cannabinoid-tolerant animals, (iv) these abstinent responses include mainly somatic signs and changes in various molecular processes affected during the abstinence to other drugs although the magnitude of these changes was currently lower in the case of cannabinoids, and (v) cannabinoid-tolerant animals do not appear to be more vulnerable to reinforcing properties of morphine, although the manipulation of the endocannabinoid signaling might serve to treat cannabis addiction and, in particular, the addiction to other drugs such as alcohol, nicotine or opioids. The present review article will address all these aspects trying to establish the bases for future research.     

Reduction of opioid dependence by the CB(1) antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction

Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB(1) antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB(1) antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB(1) antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB(1) receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB(1) antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction.     

The endogenous opioid system: A common substrate in drug addiction

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.     

The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Background  

Initial hypotheses regarding the role of the κ opioid system in drug addiction suggested that κ receptor stimulation had anti-addictive effects. However, recent research suggests that κ receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of κ receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of κ receptor ligands in drug addiction.     

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the μ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.     

Role of cannabinoid receptor in the brain as it relates to drug reward

Understanding of cannabinoid (CB) actions has been remarkably advanced during the last decade, due mainly to the identification of the G-protein-coupled cannabinoid receptors, namely, CB1 receptors that are predominantly found in the brain and CB2 receptors that are exclusively found in peripheral tissues. Endogenous ligands for these receptors have also been identified. Research to date suggests that the analgesic effect of cannabinoids and the enhancement of opioid analgesia by cannabinoids are both CB1 receptor-mediated via the activation of opioid receptors. The involvement of the CB1 receptor in mediating reinforcing and physical dependence-producing effects of opioids has also been suggested, with the former being considered the result of interaction with the dopaminergic neurotransmission in the midbrain dopamine system. However, the discriminative stimulus effects of cannabinoids have been reported to be highly specific in that the effects were not substituted by other classes of compounds including opioidergic and dopaminergic agents nor were they antagonized by antagonists of various neurotransmission systems, suggesting that the discriminative stimulus effects only involve the cannabinoid system. Thus the cannabinoid actions appear to be classifiable into at least two kinds: 1) those mediated directly through cannabinoid receptors and 2) those mediated indirectly through other systems such as opioidergic systems. Detailed research into these actions may help to elucidate not only the mechanisms of action of exogenous cannabinoids but also the role of endogenous cannabinoids, especially in the brain reward system.     

The role of the endogenous cannabinoid system in drug addiction

This review aims to present the more recent knowledge on the role of the endocannabinoid system in drug addiction. For a long time, dopamine has been consistently associated with the reinforcing effects of most drugs of abuse but, recently, pharmacological evidence points to the possibility that pharmacological management of the endocannabinoid system might not only block the direct reinforcing effect of cannabis, opioids, nicotine and ethanol, but also prevent the relapse to various drugs of abuse including opioids, cocaine, nicotine, alcohol and amphetamine. Preclinical and clinical studies suggest that the manipulation of the endocannabinoid system through the CB(1) receptor antagonist SR-141716A (rimonabant) might constitute a new therapeutical strategy for treating addiction across different classes of abused drugs.     

Cannabis: discrimination of "internal bliss"?

The recent discovery of arachidonylethanolamide (anandamide), an endogenous ligand for cannabinoid receptors, and the synthesis of SR141716A, a cannabinoid antagonist selective for brain cannabinoid (CB1) receptors, have provided new tools to explore the mechanisms underlying cannabis abuse and dependence. Drug discrimination is the animal model with the most predictive validity and specificity for investigation of the psychoactive effects of cannabinoids related to their abuse potential, because, unlike many other drugs of abuse, delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient of marijuana, is not self-administered by animals. Results of delta9-THC discrimination studies have revealed that the subjective effects of cannabis intoxication are pharmacologically selective for centrally active cannabinoid compounds, and that cannabis action at CB1 receptors is involved in medication of these effects. Less clear is the role of endogenous cannabinoid system(s) in cannabis intoxication. Anandamide, named for a Sanskrit word for "internal bliss," unreliably substitutes for delta9-THC. Further, substitution, when it is observed, occurs only at doses that also significantly decrease response rates. In contrast, delta9-THC and other structurally diverse cannabinoids fully substitute for delta9-THC at doses that do not substantially affect response rates. Attempts to train animals to discriminate anandamide (or SR141716A) have so far been unsuccessful. Preliminary evidence from drug discrimination studies with more metabolically stable anandamide analogs have suggested that these differences in the discriminative stimulus effects of delta9-THC and anandamide-like cannabinoids are not entirely due to pharmacokinetic factors, but the exact role of "internal bliss" in cannabis intoxication and dependence is still not completely understood.     

Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats

The Nociceptin/OrphaninFQ (NOP) system is believed to be involved in drug abuse and addiction. We have recently demonstrated that activation of the NOP receptor, by systemic administration of the NOP receptor agonist Ro65-6570, attenuated the rewarding effect of various opioids in conditioned place preference (CPP) in rats and this attenuating effect was reversed by the NOP receptor antagonist J-113397. The present study demonstrates that co-administration of J-113397 (4.64 mg/kg, i.p.) during conditioning, facilitates morphine-induced CPP. Moreover, we found that NOP receptor knockout rats (oprl1(-/-)) are more sensitive to the rewarding effect of morphine than wildtype control rats. Thus, pharmacological or genetic inactivation of the NOP system rendered rats more susceptible to the rewarding effect of morphine. These findings support the suggestion that the endogenous NOP system attenuates the rewarding effect of opioids and therefore offers a therapeutic target for the treatment of drug abuse and addiction.     

Endocannabinoid system involvement in brain reward processes related to drug abuse.

Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of non-cannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.     

New perspectives in the studies on endocannabinoid and cannabis: a role for the endocannabinoid-arachidonic acid pathway in drug reward and long-lasting relapse to drug taking

Growing evidence on the involvement of cannabinoids in the rewarding effects of various kinds of drugs of abuse has suggested that not only the classical dopaminergic and opioidergic, but also the most recently established endocannabinoid system is implicated in the brain reward system. Furthermore, the interplay between the three systems has been shown to be an essential neural substrate underlying many aspects of drug addiction including craving and relapse. Relapse, the resumption of drug taking following a period of drug abstinence, is considered the main hurdle in treating drug addiction. Yet, little is known about its underlying mechanisms. The link between the endocannabinoid system and the arachidonic cascade is currently being clarified. While several findings have, indeed, shown the essential role of the endocannabinoid system in the reinstatement model, the endocannabinoid-arachidonic acid pathway may also be an important part in the neural machinery underlying relapse. This evidence may provide an alternative approach that will open a novel strategy in combating drug addiction.