Morphine-context associative memory and locomotor sensitization in mice are modulated by sex and context in a dose-dependent manner

Sex differences in opioid use, development of opioid used disorder, and relapse behaviors indicate potential variations in opioid effects between men and women. The locomotor and interoceptive effects of opioids play essential roles in opioid addiction, and uncovering the neural mechanisms underlying these effects remain crucial for developing effective treatments. In this study, we examined the dose-dependent effects of morphine on locomotor sensitization and the strength and stability of morphine-context associations in the conditioned place preference (CPP) paradigm in male and female mice, as well as the relationships between these measures. We observed that while CPP is similar between sexes, the locomotor effects of repeated morphine administration and withdrawal differentially contributed to the strength and stability of morphine-context associations. Specifically, females exhibited higher morphine-induced hyperlocomotion than males regardless of the context in which morphine was experienced. Greater locomotor sensitization to morphine in females than males emerged in a dose-dependent manner only when there was sufficient context information for CPP to be established. Additionally, the relationships between the locomotor effects of morphine and the strength and stability of CPP were different in males and females. In females, positive acute and sensitizing locomotor effects of morphine were correlated with a higher CPP score, while the opposite direction of this relationship was found in males. These results suggest that different aspects of the subjective experience of morphine intoxication and withdrawal are important for morphine abuse-related behaviors and highlight the importance of sex-specific responses in the context of opioid addiction.