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Updated: Jan 14, 2026

Intracranial Pharmacotherapy and Pain Assays in Rodents
Published on: April 9, 2019
Agmatine ameliorates morphine-induced behavioral sensitization through blood-brain barrier protection and
Haotian Ma1,2,3, Wenrong Tian1,2, Jing Xiao4
1NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, China.
Abstract:
The treatment of morphine addiction remains a significant clinical challenge, and the development of novel pharmacotherapies for opioid use disorder (OUD) is imperative. Agmatine, an endogenous neuromodulator, has promising antiaddictive potential, although its precise mechanisms remain incompletely characterized. In this study, a single morphine-induced behavioral sensitization model was established in mice, and immunofluorescence staining, transmission electron microscopy (TEM), RNA sequencing and network pharmacology were used to explore the mechanism of the anti-morphine addiction effects of agmatine. We found that agmatine improved morphine-induced behavioral sensitization without affecting spontaneous activity in mice and improved the changes in synapses in the NAc induced by morphine exposure. Network pharmacological analysis revealed that the key targets associated with agmatine-morphine dependence included TNF-α, IL-6 and IL-1β. Morphine exposure can lead to increased expression of these inflammatory factors, which are closely related with the M1 microglia. Agmatine administration significantly reduced morphine-induced neuroinflammation and activation of microglia. RNA sequencing revealed that the hub genes included TEK receptor tyrosine kinase (TEK), cadherin 5 (CDH5), platelet and endothelial cell adhesion molecule 1 (PECAM1) and so on, which are closely related to endothelial adhesion and angiogenesis. Morphine exposure can downregulate the expression of VE-cadherin, Pecam1, claudin-5, occludin and ZO-1, disrupt the integrity of the BBB and increase its permeability, whereas agmatine can protect the BBB. Agmatine reversed morphine induced BBB leakage and reduced NAc infiltration of peripheral cytokines. This study revealed that agmatine mitigates morphine-induced behavioral sensitization through anti-inflammatory and BBB protection in the NAc and thus provides mechanistic evidence for the development of therapeutic agents for OUD.
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