Sinomenine Protects Against Morphine Dependence through the NMDAR1/CAMKII/CREB Pathway: A Possible Role of Astrocyte-Derived Exosomes.

Abstract

Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of morphine dependence has not been reported yet. In this study, we found that sinomenine prevented the morphine-induced conditionedplace preference in mice. Sinomenine reduced the levels of cAMP and intracellular Ca2+ in morphine-treated SH-SY5Y cells. Moreover, sinomenine inhibited the expressions of p-NMDAR1/NMDAR1, p-CAMKII/CAMKII, and p-CREB/CREB in the hippocampusof morphine-dependent mice and SH-SY5Y cells. Furthermore, we found that sinomenine inhibitedthe morphine-induced activation of astrocytesin vivo and in vitro. Afterwards, exosomes were isolated from cultured primary astrocytes treated with phosphate buffer saline (PBS, ctl-exo), morphine (mor-exo), or morphine and sinomenine (Sino-exo). Subsequently, morphine-treated SH-SY5Y cells were treated with ctl-exo, mor-exo, and Sino-exo. Results showed that Sino-exo reduced the level of cAMP, intracellular Ca2+, and the expression of p-CAMKII/CAMKII and p-CREB/CREB in morphine-treated SH-SY5Y cells. In conclusion, we demonstrated that sinomenine exhibited protective effects against morphine dependencein vivo and in vitro through theNMDAR1/CAMKII/CREB pathway. Sinomenine-induced alterationof the function of astrocyte-derived exosomes may contribute to the antidependence effects of sinomenine in morphine dependence.

• Authors: Jinying Ou, Yuting Zhou, Chan Li, Zhijie Chen, Hancheng Li, Miao Fang, Chen Zhu, Chuying Huo, Ken Kin-Lam Yung, Jing Li, Chaohua Luo, Zhixian Mo
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 9 (Sep 17 2018) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30227624 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Cyclic AMP Response Element-Binding Protein
• Morphinans
• NMDA receptor A1
• Protective Agents
• Receptors, N-Methyl-D-Aspartate
• sinomenine
• Cyclic AMP
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium

Topics

• Animals
• Astrocytes (drug effects, metabolism, ultrastructure)
• Biomarkers (metabolism)
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cell Line, Tumor
• Choice Behavior
• Conditioning, Psychological
• Cyclic AMP (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Exosomes (drug effects, metabolism, ultrastructure)
• Hippocampus (drug effects, metabolism)
• Humans
• Intracellular Space (metabolism)
• Male
• Mice
• Morphinans (pharmacology)
• Morphine Dependence (metabolism, pathology)
• Nanoparticles (chemistry, ultrastructure)
• Particle Size
• Phosphorylation (drug effects)
• Protective Agents (pharmacology)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Signal Transduction (drug effects)