Neuroimaging revealed long-lasting glucose metabolism changes to morphine withdrawal in rats pretreated with the cannabinoid agonist CP-55,940 during periadolescence

This study evaluates the long-term effects of a six and 14-week morphine withdrawal in rats pretreated with a cannabinoid agonist (CP-55,940, CP) during periadolescence. Wistar rats (33 males; 32 females) were treated with CP or its vehicle (VH) from postnatal day (PND) 28–38. At PND100, rats performed morphine self-administration (MSA, 15d/12 h/session). Eight groups were defined according to pretreatment (CP), treatment (morphine), and sex. Three [18F]FDG-PET brain images were acquired: after MSA, and after six and 14 weeks of withdrawal. PET data were analyzed with SPM12. Endocannabinoid (EC) markers were evaluated in frozen brain tissue at endpoint. Females showed a higher mean number of self-injections than males. A main Sex effect on global brain metabolism was found. FDG uptake in males was discrete, whereas females showed greater brain metabolism changes mainly in areas of the limbic system after morphine treatment. Moreover, the morphine-induced metabolic pattern in females was exacerbated when CP was previously present. In addition, the CP-Saline male group showed reduced CB1R, MAGL expression, and NAPE/FAAH ratio compared to the control group, and morphine was able to reverse CB1R and MAGL expression almost to control levels. In conclusion, females showed greater and longer-lasting metabolic changes after morphine withdrawal than males, indicating a higher vulnerability and a different sensitivity to morphine in subjects pre-exposed to CP. In contrast, males primarily showed changes in EC markers. Together, our results suggest that CP pre-exposure contributes to the modulation of brain metabolism and EC systems in a sex-dependent manner