The endocannabinoid system in the hippocampus showed opposite patterns during morphine reward expression versus relapse, with enzymes breaking down endocannabinoids increasing during reward and CB1 receptors increasing during relapse.
Read this if you are interested in how the brain's cannabinoid system relates to opioid addiction and relapse.
Endocannabinoid degradation enzymes increased during reward; CB1 receptors increased during relapse
What the researchers found
This study examined how endocannabinoid-related genes in the hippocampus change across three phases of morphine addiction: initial reward, extinction, and relapse.
During the expression of morphine reward (conditioned place preference), the hippocampus showed increased expression of FAAH and MAGL, the enzymes that break down the two main endocannabinoids (anandamide and 2-AG). At the same time, CB1 and CB2 receptor expression decreased. This pattern suggests active degradation of endocannabinoid signaling during morphine reward.
During relapse (reinstatement of morphine preference), the pattern reversed: MAGL decreased while CB1 receptor expression increased. This opposite pattern suggests the endocannabinoid system reorganizes between initial drug reward and relapse.
The enzymes that create endocannabinoids (NAPEPLD and DAGL) did not change in any condition, meaning the shifts were driven by changes in degradation and receptor expression rather than production.
Why it matters
Understanding how the endocannabinoid system changes during different phases of opioid addiction could lead to phase-specific treatments. The finding that relapse involves different endocannabinoid changes than initial reward suggests that targeting the endocannabinoid system for relapse prevention would require a different approach than targeting initial drug effects.
The numbers in context
During CPP expression: FAAH and MAGL mRNA increased, CB1R and CB2R decreased. During reinstatement: MAGL decreased, CB1R increased. Biosynthetic enzymes (NAPEPLD, DAGLa/b) unchanged across all conditions.
How the study worked
Mice underwent morphine conditioned place preference (CPP) training, followed by extinction and reinstatement. Quantitative RT-PCR measured expression of endocannabinoid-related genes (CB1R, CB2R, FAAH, MAGL, NAPEPLD, DAGLa/b) in the dorsal hippocampus at each phase.
What this study cannot tell us
Gene expression changes do not necessarily translate to protein level or functional changes. The study measured mRNA only, not endocannabinoid levels or receptor activity. Mouse conditioned place preference is a model of drug reward but does not capture all aspects of human addiction.
How to read the evidence
Animal study measuring gene expression changes across addiction phases. Preliminary because mRNA changes may not reflect functional outcomes.
When this study was published
Published in 2017.
The bigger picture
The opioid crisis has created urgent demand for understanding addiction mechanisms and developing new treatments. This study reveals that the endocannabinoid system, which interacts closely with opioid pathways, undergoes dynamic reorganization across addiction stages, providing potential therapeutic targets.
Questions still open
- Could FAAH inhibitors prevent morphine reward by maintaining anandamide levels? Would CB1 receptor antagonists specifically prevent relapse by blocking the increased CB1 signaling? Do these hippocampal changes parallel changes in other brain regions involved in addiction?
Common questions
How does the endocannabinoid system relate to opioid addiction?
Could targeting the endocannabinoid system help treat opioid addiction?
Read the original research
Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.
Neuroscience letters, 643, 38-44
Citation
Li, Wei; Zhang, Cong-Li; Qiu, Zheng-Guo. (2017). Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.. Neuroscience letters, 643, 38-44. https://doi.org/10.1016/j.neulet.2017.02.025
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