Cannabinoids: Drug or Medication?

This chapter aims at exploring the use and misuse of cannabinoids as it has become a major societal issue. In the first section, we describe the historical use of cannabis as a natural cure in ancient civilizations. We then explore the current use of cannabinoids in medicine, which includes innovative strategies for treating various diseases such as multiple sclerosis or cancer‐induced pain. In the second section, we consider how the discovery and characterization of the endocannabinoid system have increased knowledge of this system\u27s mode of action. Consumption of cannabis for recreational use however is a significant public health issue today. Scientific advances are confronted with the adverse health effects that are demonstrated in preclinical and clinical studies based on the psychotic and addictive properties of this compound. In the third section, we therefore provide an overview of the recent findings on the endocannabinoid system using animal models with proposed molecular mechanisms and potential interactions with other neuromodulatory systems like the opioid system. Finally, through alternative strategies to current treatments with both phyto‐ and synthetic cannabinoids, we try to reconcile the beneficial aspects of the use of cannabinoids for medication and the aspects associated with addictive properties

Troubles de l’alimentation

Les troubles du comportement alimentaire altèrent le circuit cérébral de la récompense et sont caractérisés par une perte du contrôle de la prise alimentaire. Ces troubles sont accompagnés de modifications neurobiologiques associées au comportement de type addictif et impliquent des processus neuro-inflammatoires qui pourraient être à l’origine du développement de douleurs chroniques.Number: 2 Publisher: Lavoisier SA

CB1 Agonism Alters Addiction-Related Behaviors in Mice Lacking Mu or Delta Opioid Receptors

Opioids are powerful analgesics but the clinical utility of these compounds is reduced by aversive outcomes, including the development of affective and substance use disorders. Opioid systems do not function in isolation so understanding how these interact with other neuropharmacological systems could lead to novel therapeutics that minimize withdrawal, tolerance, and emotional dysregulation. The cannabinoid system is an obvious candidate as anatomical, pharmacological, and behavioral studies point to opioid-cannabinoid interactions in the mediation of these processes. The aim of our study is to uncover the role of specific cannabinoid and opioid receptors in addiction-related behaviors, specifically nociception, withdrawal, anxiety, and depression. To do so, we tested the effects of a selective CB1 agonist, arachidonyl-2-chloroethylamide (ACEA), on mouse behavior in tail immersion, naloxone-precipitated withdrawal, light-dark, and splash tests. We examined cannabinoid-opioid interactions in these tests by comparing responses of wildtype (WT) mice to mutant lines lacking either Mu or Delta opioid receptors. ACEA, both acute or repeated injections, had no effect on nociceptive thresholds in WT or Mu knockout (KO) mice suggesting that analgesic properties of CB1 agonists may be restricted to chronic pain conditions. The opioid antagonist, naloxone, induced similar levels of withdrawal in all three genotypes following ACEA treatment, confirming an opioidergic contribution to cannabinoid withdrawal. Anxiety-like responses in the light-dark test were similar across WT and KO lines; neither acute nor repeated ACEA injections modified this behavior. Similarly, administration of the Delta opioid receptor antagonist, naltrindole, alone or in combination with ACEA, did not alter responses of WT mice in the light-dark test. Thus, there may be a dissociation in the effect of pharmacological blockade vs. genetic deletion of Delta opioid receptors on anxiety-like behavior in mice. Finally, our study revealed a biphasic effect of ACEA on depressive-like behavior in the splash test, with a prodepressive state induced by acute exposure, followed by a shift to an anti-depressive state with repeated injections. The initial pro-depressive effect of ACEA was absent in Mu KO mice. In sum, our findings confirm interactions between opioid and cannabinoid systems in withdrawal and reveal reduced depressive-like symptoms with repeated CB1 receptor activation

Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury.

BACKGROUND: Rat oligonucleotide microarrays were used to detect changes in gene expression in the dorsal root ganglion (DRG) 3 days following sciatic nerve transection (axotomy). Two comparisons were made using two sets of triplicate microarrays, naïve versus naïve and naïve versus axotomy. RESULTS: Microarray variability was assessed using the naïve versus naïve comparison. These results support use of a P < 0.05 significance threshold for detecting regulated genes, despite the large number of hypothesis tests required. For the naïve versus axotomy comparison, a 2-fold cut off alone led to an estimated error rate of 16%; combining a >1.5-fold expression change and P < 0.05 significance reduced the estimated error to 5%. The 2-fold cut off identified 178 genes while the combined >1.5-fold and P < 0.05 criteria generated 240 putatively regulated genes, which we have listed. Many of these have not been described as regulated in the DRG by axotomy. Northern blot, quantitative slot blots and in situ hybridization verified the expression of 24 transcripts. These data showed an 83% concordance rate with the arrays; most mismatches represent genes with low expression levels reflecting limits of array sensitivity. A significant correlation was found between actual mRNA differences and relative changes between microarrays (r(2 )= 0.8567). Temporal patterns of individual genes regulation varied. CONCLUSIONS: We identify parameters for microarray analysis which reduce error while identifying many putatively regulated genes. Functional classification of these genes suggest reorganization of cell structural components, activation of genes expressed by immune and inflammatory cells and down-regulation of genes involved in neurotransmission

Addiction: A neurobiological and cognitive brain disorder

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Neuroepigenetics and addictive behaviors: Where do we stand?

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Reward processing by the opioid system in the brain.

International audienceThe opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder

Deletion of mu opioid receptors reduces palatable solution intake in a mouse model of binge eating

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The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

International audienceDelta-selective agonists have been developed to produce potent analgesic compounds with limited side-effects. DPDPE and deltorphin II are considered prototypes, but their delta-selectivity in vivo and the true ability of delta receptors to produce analgesia remain to be demonstrated. Here we have performed a parallel analysis of mu, delta and combinatorial opioid receptor knockout mice, in which we found no obvious alteration of G-protein coupling for remaining opioid receptors. We compared behavioural responses in two models of acute thermal pain following DPDPE and deltorphin II administration by intracerebroventricular route. In the tail-immersion test, both compounds were fully analgesic in delta knockout mice and totally inactive in mu knockout mice. In the hotplate test, the two compounds again produced full analgesia in delta knockout mice. In mu knockout mice, there was significant, although much lower, analgesia. Furthermore, DPDPE analgesia in the delta knockout mice was fully reversed by the mu selective antagonist CTOP in both tests. Together, this suggests that mu rather than delta receptors are recruited by the two agonists for the tail withdrawal and the hotplate responses. Finally, deltorphin II slightly prolonged jump latencies in double mu/kappa knockout mice (delta receptors only) and this response was abolished in the triple knockout mice, demonstrating that the activation of delta receptors alone can produce weak but significant mu-independent thermal antinociception

The endocannabinoid system is modulated in reward and homeostatic brain regions following diet-induced obesity in rats: a cluster analysis approach

International audienceObjectives: Increased availability of high-calorie palatable food in most countries has resulted in overconsumption of these foods, suggesting that excessive eating is driven by pleasure, rather than metabolic need. The behavior contributes to the rise in eating disorders, obesity, and associated pathologies like diabetes, cardiac disease, and cancers. The mesocorticolimbic dopamine and homeostatic circuits are interconnected and play a central role in palatable food intake. The endocannabinoid system is expressed in these circuits and represents a potent regulator of feeding, but the impact of an obesogenic diet on its expression is not fully known.Methods: Food intake and body weight were recorded in male Wistar rats over a 6-week free-choice regimen of high fat and sugar; transcriptional regulations of the endocannabinoid system were examined post-mortem in brain reward regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, and arcuate nucleus). K-means cluster analysis was used to classify animals based on individual sensitivity to obesity and palatable food intake. Endocannabinoid levels were quantified in the prefrontal cortex and nucleus accumbens. Gene expression in dopamine and homeostatic systems, including ghrelin and leptin receptors, and classical homeostatic peptides, were also investigated.Results: The free-choice high-fat -and sugar diet induced hyperphagia and obesity in rats. Cluster analysis revealed that the propensity to develop obesity and excessive palatable food intake was differently associated with dopamine and endocannabinoid system gene expression in reward and homeostatic brain regions. CB2 receptor mRNA was increased in the nucleus accumbens of high sugar consumers, whereas CB1 receptor mRNA was decreased in obesity prone rats.Conclusions: Transcriptional data are consistent with observations of altered dopamine function in rodents that have access to an obesogenic diet and point to cannabinoid receptors as GPCR targets involved in neuroplasticity mechanisms associated with maladaptive intake of palatable food