Role of SK3 channels in the nucleus accumbens core in modulating opioid-induced addiction behaviors

Minglong Zhang; Jian Wang; Hongyu Yang; Yun Lu; Hailei Yu; Bing Xie; Ludi Zhang; Bin Cong; Chunling Ma; Di Wen

doi:10.1016/j.neuropharm.2025.110720

Role of SK3 channels in the nucleus accumbens core in modulating opioid-induced addiction behaviors

Neuropharmacology. 2026 Jan 1:282:110720. doi: 10.1016/j.neuropharm.2025.110720. Epub 2025 Oct 17.

Authors

Minglong Zhang¹, Jian Wang², Hongyu Yang³, Yun Lu², Hailei Yu², Bing Xie², Ludi Zhang², Bin Cong², Chunling Ma⁴, Di Wen⁵

Affiliations

¹ Department of Genetics, Qiqihar Medical University, Heilongjiang Provincial Key Laboratory of Food & Medicine Homology and Metabolic Disease Prevention, Heilongjiang Province, Qiqihar, 161006, PR China; College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China.
² College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China.
³ College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China; Bethune Int Peace Hosp, Hebei Province, Shijiazhuang 050000, PR China.
⁴ College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China. Electronic address: chunlingma@hebmu.edu.cn.
⁵ College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei Province, Shijiazhuang, 050017, PR China. Electronic address: wendi01125@hebmu.edu.cn.

PMID: 41110633
DOI: 10.1016/j.neuropharm.2025.110720

Abstract

Opioid addiction remains a critical public health challenge, yet the underlying neurobiological mechanisms remain incompletely understood. This study investigated the role of small-conductance calcium-activated potassium (SK) channels in the nucleus accumbens core (NAcC) in opioid-related behaviors. Using conditioned place preference (CPP) and intravenous self-administration (IVSA) models in mice, we observed a reduction in the excitability of NAcC medium spiny neurons (MSNs) concomitant with an increase in SK3 channel expression and SK-mediated currents during morphine-induced CPP. Pharmacological activation of SK channels with 1-EBIO enhanced morphine CPP, whereas blockade with apamin attenuated it. Viral-mediated SK3 overexpression in NAcC potentiated both morphine CPP and heroin IVSA, while SK3 knockdown suppressed these behaviors. Electrophysiological recordings confirmed that SK3 modulation bidirectionally regulated MSN excitability and medium afterhyperpolarization (mAHP). These findings demonstrate that SK3 channels in NAcC critically regulate opioid reward and reinforcement by modulating neuronal excitability, suggesting SK3 channel as a potential therapeutic target for opioid addiction.

Keywords: Addiction; Medium spiny neurons; Nucleus accumbens; Opioids; SK3 channels.

MeSH terms

Analgesics, Opioid* / administration & dosage
Analgesics, Opioid* / pharmacology
Animals
Apamin / pharmacology
Behavior, Addictive* / metabolism
Heroin / administration & dosage
Male
Mice
Mice, Inbred C57BL
Morphine / administration & dosage
Morphine / pharmacology
Neurons / drug effects
Neurons / metabolism
Neurons / physiology
Nucleus Accumbens* / drug effects
Nucleus Accumbens* / metabolism
Opioid-Related Disorders* / metabolism
Opioid-Related Disorders* / physiopathology
Reward
Self Administration
Small-Conductance Calcium-Activated Potassium Channels* / metabolism

Substances

Small-Conductance Calcium-Activated Potassium Channels
Morphine
Analgesics, Opioid
Kcnn3 protein, mouse
Apamin
Heroin