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Psychopharmacology (Berl). 2019 Sep;236(9):2557-2568. doi: 10.1007/s00213-019-05226-y. Epub 2019 Mar 22.

Unidirectional opioid-cannabinoid cross-tolerance in the modulation of social play behavior in rats.

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Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy.
Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy.
Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Viale G. Marconi 446, 00146, Rome, Italy.



The endocannabinoid and the endogenous opioid systems interact in the modulation of social play behavior, a highly rewarding social activity abundantly expressed in young mammals. Prolonged exposure to opioid or cannabinoid receptor agonists induces cross-tolerance or cross-sensitization to their acute behavioral effects.


Behavioral and biochemical experiments were performed to investigate whether cross-tolerance or cross-sensitization occurs to the play-enhancing effects of cannabinoid and opioid drugs on social play behavior, and the possible brain substrate involved.


The play-enhancing effects induced by systemic administration of JZL184, which inhibits the hydrolysis of the endocannabinoid 2-AG, were suppressed in animals repeatedly pretreated with the opioid receptor agonist morphine. Conversely, acute morphine administration increased social play in rats pretreated with vehicle or with either JZL184 or the cannabinoid agonist WIN55,212-2. Acute administration of JZL184 increased the activation of both CB1 receptors and their effector Akt in the nucleus accumbens and prefrontal cortex, brain regions important for the expression of social play. These effects were absent in animals pretreated with morphine. Furthermore, only animals repeatedly treated with morphine and acutely administered with JZL184 showed reduced activation of CB1 receptors and Akt in the amygdala.


The present study demonstrates a dynamic opioid-cannabinoid interaction in the modulation of social play behavior, occurring in limbic brain areas strongly implicated in social play behavior. A better understanding of opioid-cannabinoid interactions in social play contributes to clarify neurobiological aspects of social behavior at young age, which may provide new therapeutic targets for social dysfunctions.


2-AG; Cannabinoid; Morphine; Opioid; Rats; Social play behavior


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