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  3. Agmatine ameliorates morphine-induced behavioral sensitization through blood-brain barrier protection and anti-neuroinflammatory effects in the nucleus accumbens

Agmatine ameliorates morphine-induced behavioral sensitization through blood-brain barrier protection and anti-neuroinflammatory effects in the nucleus accumbens

  • Psychopharmacology (Berl). 2025 Oct 24. doi: 10.1007/s00213-025-06944-2.
Haotian Ma # 1 2 3,  Wenrong Tian # 1 2,  Jing Xiao 4,  Xilin Shao 1 2,  Jincen Liu 1 2,  Xinyue Yan 1 2,  Jie Zhu 5 6,  Jianghua Lai 7 8
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, China.
  • 2 Bio-evidence Sciences Academy, Western China Science and Technology, Innovation Harbor, Xi'an Jiaotong University, Xi'an, China.
  • 3 School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 4 NHC Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China.
  • 5 NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 6 Bio-evidence Sciences Academy, Western China Science and Technology, Innovation Harbor, Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 7 NHC Key Laboratory of Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 8 Bio-evidence Sciences Academy, Western China Science and Technology, Innovation Harbor, Xi'an Jiaotong University, Xi'an, China. [email protected].
  • # Contributed equally.
PMID: 41134339 DOI: 10.1007/s00213-025-06944-2
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.

Keywords

Agmatine; Behavioral sensitization; Blood-Brain barrier; Morphine; Neuroinflammation.

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