Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine

The opioid and cannabinoid systems co-operate to regulate physiological processes such as nociception and reward. The endocannabinoid system may be a component of the brain reward circuitry and thus play a role not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal for other misused drugs. We provide evidence of a cannabinoid mechanism in an animal model of morphine drug-seeking behaviour, referred to as behavioural sensitization. The present study was designed to test the effects of the CB₁ cannabinoid receptor antagonist SR141716A in two different phases of morphine sensitization (induction and expression) and to measure the brain contents of arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), the two main endogenous ligands for cannabinoid receptors in the different phases of morphine sensitization. The cannabinoid antagonist modified the signs of morphine sensitization when administered in the expression phase, whereas co-administration of SR141716A and morphine in the induction phase only slightly affected the behavioural responses, suggesting that CB₁ receptor blockade attenuates the behavioural manifestations of morphine sensitization but not its development. AEA and 2-AG were affected differently by morphine during the two phases of behavioural sensitization. The alterations were in opposite directions and specific for the cerebral area analysed (caudate putamen, nucleus accumbens, hippocampus and prefrontal cortex). The results suggest that the endocannabinoid system undergoes profound changes during the different phases of sensitization to morphine in rats, providing a possible neurochemical basis for the previously observed cross-sensitization between opiates and cannabinoids.