Tolerance to the reinforcing effects of morphine in delta9-tetrahydrocannabinol treated mice

Abstract

Several studies have investigated interactions between opioid and cannabinoid systems. However, the results regarding the rewarding effects of opiates in animals pre-exposed to CB1 agonists, appear inconsistent. Using the conditioned place preference, it was shown that dependence to delta9-tetrahydrocannabinol (THC) was hardly reached, while the synthetic ligand WIN55,212-2 facilitate the rewarding effects of morphine. The aim of the present study was to establish whether a chronic THC treatment (10 mg/kg, i.p., 21 days) may facilitate, in mice, the rewarding effects of morphine used at low doses (0.5 and 2 mg/kg, i.p.) or high dose (10 mg/kg, i.p.) after a long drug-free period, as it was speculated that chronic cannabinoid exposure may induce long-lasting neural changes in brain regions involved in opiate addiction. Moreover, THC was used in conditions as close as possible to those leading to cannabis drawbacks. After 15 days of abstinence, the locomotor activating properties of morphine as well as its motivational properties were not facilitated by pretreatment with THC in mice and even reduced for the higher dose of morphine used in the conditioned place preference (CPP). This lack of CPP in animals pretreated with THC was not due to discrimination impairment between different environments, as demonstrated in a two-trial recognition task. In conclusion, it appears that chronic THC treatment leads to a reduction of reinforcing effects of morphine in the CPP. This result supports the occurrence of modulatory interaction between opioid and cannabinoid systems in the reward process.