Abstract
Opioid abuse is a growing global problem. Current therapies for opioid abuse target withdrawal symptoms and have several adverse side effects. There are no treatments to address opioid-induced neural adaptations associated with abuse and addiction. Preclinical research demonstrates interactions between the endogenous opioid and cannabinoid systems, suggesting that cannabinoids may be used to treat opioid addiction and dependence. The aim of this review is to assess how cannabinoids affect behavioural and molecular measures of opioid dependence and addiction-like behaviour in animal models. It appears that cannabidiol and cannabinoid receptor 1 (CB1R) antagonists have potential for treating drug-craving and drug-seeking behaviour, based on evidence from preclinical animal models. Ligands which inhibit the action of cannabinoid degradation enzymes also show promise in reducing opioid withdrawal symptoms and opioid self-administration in rodents. Agonists of CB1R could be useful for treating symptoms of opioid withdrawal; however, the clinical utility of these drugs is limited by side effects, the potential for cannabinoid addiction and an increase in opiate tolerance induced by cannabinoid consumption. The mechanisms by which cannabinoids reduce opioid addiction-relevant behaviours include modulation of cannabinoid, serotonin, and dopamine receptors, as well as signalling cascades involving ERK-CREB-BDNF and peroxisome proliferator-activated receptor-α. Identifying the receptors involved and their mechanism of action remains a critical area of future research.
Highlights
There has been a growing trend of opioid dependence and abuse in Australia [1], and globally there were an estimated 26.8 million people with opioid abuse disorder in 2016 [2]
The doses used in this study decrease responding for a food reinforcer [73], which may suggest CP 55,940 and WIN 55,212-2 reduce locomotor activity in general, and confound the interpretation that these agonists limit heroin self-administration. These results indicate that CB1R agonists often increase opioid reward
While infusions of CBD alone into the ventral hippocampus do not affect subthreshold morphine conditioned place preference (CPP), infusions of CBD in the ventral hippocampus reverse THC’s enhancement of subthreshold morphine reward, and these effects are mediated by modulation of extracellular signal-regulated kinase (ERK) phosphorylation [57]. This suggests CBD may reduce THC’s enhancement of morphine reward via ERK signalling in the ventral hippocampus [57]. These results indicate that CBD can reduce the rewarding effects of opioids, and these effects can be mediated by 5-HT1A and/or D4 receptors
Summary
There has been a growing trend of opioid dependence and abuse in Australia [1], and globally there were an estimated 26.8 million people with opioid abuse disorder in 2016 [2]. The doses used in this study decrease responding for a food reinforcer [73], which may suggest CP 55,940 and WIN 55,212-2 reduce locomotor activity in general, and confound the interpretation that these agonists limit heroin self-administration These results indicate that CB1R agonists often increase opioid reward. The effects of OlGly on morphine withdrawal were mediated by CB1R and PPARα [99], indicating that increasing endogenous cannabinoid levels could be a potential treatment option for opioid dependence. HU595 does not produce rewarding or aversive effects on its own and does not modify locomotor activity, supporting its therapeutic utility [100] Together, these studies demonstrate that FAAH inhibitors may act via increasing CB1R and PPARα signalling to limit opioid withdrawal behaviours in rodents. This preliminary research supports future investigations into CB2R agonists for the treatment of opiate withdrawal and reward is warranted, and the mechanisms by which this occurs
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