Cannabidiol as an adjunct strategy in opioid-use disorder: dissociable effects on physical dependence, psychological effects of withdrawal and drug-seeking behaviour

Introduction

For several decades, opioid prescribing has increased substantially worldwide, leading to a rise in opioid use disorders. Indeed, prolonged opioid use in pain management leads to serious adverse effects, such as addictive, anxiety-like, and depressive-like behaviors, which are associated with persistent neuroinflammation in the brain; this neuroinflammation, in turn, further exacerbates these adverse effects. Previous studies have shown the therapeutic potential of cannabinoids to enhance the analgesic effects of opioids, as well as to reduce some side effects induced by opioids. However, the mechanisms of action involved remain unknown.

Objectives

This project aims to evaluate cannabidiol (CBD) (a cannabinoid devoid of psychoactive effects), known for its anti-inflammatory properties, as an innovative therapeutic strategy to reduce these opioid-induced side effects.

Methods

Experiments were conducted in adult male C57BL/6JRj mice. Morphine dependence was promoted with a 6-days treatment (twice daily injection, intraperitoneally (i. p.)) with escalating dose (dose 10 mg/kg, dose 20 mg/kg, dose 30 mg/kg, dose 40 mg/kg, dose 50 mg/kg). Mice were treated with CBD at two doses (10 or 20 mg/kg, i. p.) during morphine exposure. Physical withdrawal was assessed following naloxone (an opioid antagonist) precipitated withdrawal. Psychological signs of withdrawal were evaluated using the forced swim test and tail suspension test at 1, 4, and 6 weeks after morphine cessation. The reinforcing effects of morphine were assessed using the conditioned place preference paradigm. Data were analyzed with Student’s t-test or one-way analysis of variance followed by Tukey’s post-hoc multiple comparison test. A p value inferior to 0.05 was considered significant.

Results

Naloxone-precipitated withdrawal elicited robust somatic signs, which were significantly attenuated by CBD when co-administrated with morphine in a dose-dependent manner. Regarding the psychological signs of withdrawal, mice demonstrated a depressive-like behavior (in the forced swim test) after 1 and 4 weeks of morphine withdrawal. Interestingly, co-administration of CBD significantly reduced this effect in an inverted dose response. In the conditioned place preference, we found that when mice received CBD (20 mg/kg) during morphine conditioning, it significantly abolished the expression of place preference. More interestingly, when conditioned place preference was extinguished, mice treated with CBD 10 mg/kg but not CBD 20 mg/kg during extinction were unable to reinstate morphine seeking triggered by a priming dose of the drug.

Conclusion: Overall, our data suggest that CBD treatment alleviates several opioid-induced adverse effects, including physical dependence, depressive-like behavior during withdrawal, and the expression of rewarding effects, even after extinction. The observation that different CBD doses are required depending on the behavioral outcome suggests the involvement of distinct underlying mechanisms, in agreement with the complex pharmacology of CBD. We are currently investigating these mechanisms, particularly in relation to neuroinflammation Moreover investigation on the effects of CBD in female mice are on-going. Indeed, preliminary data suggest differential response to CBD depending on sex.

References

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