CB1 receptor levels increased in the brain reward center during morphine withdrawal in rats | Research

The takeaway

Rats undergoing morphine withdrawal showed increased CB1 receptor expression in the nucleus accumbens, a brain reward center, across all withdrawal phases, and blocking these receptors reduced drug-seeking behavior.

Read this if you are interested in the neuroscience of how the endocannabinoid system interacts with opioid addiction and withdrawal.

CB1 receptors elevated across all three phases of morphine withdrawal

What the researchers found

Researchers examined CB1 cannabinoid receptor expression in the nucleus accumbens core (a key brain reward region) of rats during acute (1 day), latent (3 days), and chronic (3 weeks) morphine withdrawal. CB1 receptor expression was significantly increased at all three time points compared to controls.

Electron microscopy revealed that CB1 receptors were primarily located on presynaptic terminals forming inhibitory (symmetrical) synapses. Both the number of CB1-positive terminals and the density of receptor particles at these terminals increased during withdrawal.

When researchers injected the CB1 receptor blocker rimonabant directly into the nucleus accumbens, it reduced conditioned place preference (a measure of drug-seeking behavior) during morphine withdrawal.

Why it matters

Relapse is one of the biggest challenges in addiction treatment. This study identified the endocannabinoid system in the nucleus accumbens as persistently altered during opioid withdrawal, suggesting it may contribute to the drug-seeking behavior that underlies relapse.

The numbers in context

CB1 receptor expression was elevated at 1 day, 3 days, and 3 weeks of morphine withdrawal. Increased receptor density was observed at inhibitory presynaptic terminals. Rimonabant infusion into the nucleus accumbens reduced conditioned place preference.

How the study worked

Rats were exposed to morphine to establish conditioned place preference, then underwent withdrawal for 1 day, 3 days, or 3 weeks. CB1 receptor expression in the nucleus accumbens core was assessed using immunofluorescence microscopy and immunoelectron microscopy. The functional role of CB1 receptors was tested by infusing the antagonist rimonabant into the nucleus accumbens during withdrawal.

What this study cannot tell us

This was an animal study in rats, and findings may not directly translate to humans. Morphine withdrawal was studied, not cannabis withdrawal. The forced morphine exposure paradigm differs from human patterns of drug use. Only one brain region was examined.

How to read the evidence

Well-conducted animal study with multiple methodologies, but findings are preclinical and require human translation.

When this study was published

Published in 2013.

The bigger picture

This study connects the endocannabinoid and opioid systems in the context of addiction and relapse. The persistent upregulation of CB1 receptors across all withdrawal phases suggests that the endocannabinoid system may play an ongoing role in maintaining drug-seeking motivation, not just during acute withdrawal.

Questions still open

Does a similar CB1 receptor upregulation occur in the human nucleus accumbens during opioid withdrawal? Would CB1 receptor blockers reduce relapse rates in human addiction treatment? Is this endocannabinoid system change specific to opioid withdrawal, or does it occur with other drugs?

Common questions

How are the cannabinoid and opioid systems connected in addiction?

This study found that CB1 cannabinoid receptors in a key brain reward region increased during opioid withdrawal, and blocking them reduced drug-seeking behavior. This suggests the endocannabinoid system may help maintain drug cravings during withdrawal.

Could cannabinoid receptor blockers help treat opioid addiction?

This animal study showed that infusing a CB1 blocker (rimonabant) into the nucleus accumbens reduced drug-seeking behavior during morphine withdrawal. However, translating this to human treatment would require extensive further research.

Read the original research

Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal.

Brain research, 1531, 102-12

View on PubMed ↗Publisher’s paper ↗

Citation

Yuan, Wei-Xin; Heng, Li-Jun; Ma, Jie; Wang, Xing-Qin; Qu, Li-Juan; Duan, Li; Kang, Jun-Jun; Chen, Liang-Wei; Gao, Guo-Dong. (2013). Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal.. Brain research, 1531, 102-12. https://doi.org/10.1016/j.brainres.2013.07.047