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.
Highlights
Drug dependence is considered as an aberrant form of learning and memory, generating strong associations that link action to drug seeking, increasing the vulnerability to relapse [1,2]
We aimed to investigate the effect of sinomenine on morphine dependence through the NMDAR1/CAMKII/CREB signaling pathway in vitro and in vivo
We found that sinomenine inhibits the activation of NMDAR1 receptors in the mouse hippocampus and in morphine-treated SH-SY5Y cells, though this effect could be counteracted by NMDA receptor agonists
Summary
Drug dependence is considered as an aberrant form of learning and memory, generating strong associations that link action to drug seeking, increasing the vulnerability to relapse [1,2]. It is crucial to reduce drug addiction-induced memory to prevent morphine dependence. The hippocampus is an important brain region for the formation of addiction memory [3]. Molecules 2018, 23, 2370 found that long-term potentiation (LTP) and long-term depression (LTD) of postsynaptic membranes of glutamatergic neurons in the hippocampus are involved in drug addiction-related behaviors, such as relapse and behavioral sensitization [4]. N-methyl-d-aspartate (NMDA) receptors, one of the excitatory glutamate receptors, take part in the formation of LTP processes in the postsynaptic membrane [5].
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