Upregulation of dynorphin/kappa opioid receptor system in the dorsal hippocampus contributes to morphine withdrawal-induced place aversion

Yan Chen1, Chen-yao Wang2,3, Gui-ying Zan2, Song-yu Yao4, Ying-zhi Deng2, Xue-lian Shu2,3, Wei-wei Wu2, Yan Ma2, Yu-jun Wang2, Chang-xi Yu1, Jing-gen Liu2
1 Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
2 CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China
3 University of Chinese Academy of Sciences, No. 19 A Yuquan Road, Beijing 100049, China
4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
Correspondence to: Yu-jun Wang:, Chang-xi Yu:,
DOI: 10.1038/s41401-022-00987-3
Received: 5 April 2022
Accepted: 22 August 2022
Advance online: 20 September 2022


Aversive emotion of opioid withdrawal generates motivational state leading to compulsive drug seeking and taking. Kappa opioid receptor (KOR) and its endogenous ligand dynorphin have been shown to participate in the regulation of aversive emotion. In the present study, we investigated the role of dynorphin/KOR system in the aversive emotion following opioid withdrawal in acute morphine-dependent mice. We found that blockade of KORs before pairing by intracerebroventricular injection of KOR antagonist norBNI (20, 40 μg) attenuated the development of morphine withdrawal-induced conditioned place aversion (CPA) behavior. We further found that morphine withdrawal increased dynorphin A expression in the dorsal hippocampus, but not in the amygdala, prefrontal cortex, nucleus accumbens, and thalamus. Microinjection of norBNI (20 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-induced CPA behavior. We further found that p38 MAPK was significantly activated in the dorsal hippocampus after morphine withdrawal, and the activation of p38 MAPK was blocked by pretreatment with norBNI. Accordingly, microinjection of p38 MAPK inhibitor SB203580 (5 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-produced CPA behavior. This study demonstrates that upregulation of dynorphin/KOR system in the dorsal hippocampus plays a critical role in the formation of aversive emotion associated with morphine withdrawal, suggesting that KOR antagonists may have therapeutic value for the treatment of opioid withdrawal- induced mood-related disorders.
Keywords: morphine withdrawal; conditioned place aversion; kappa opioid receptor; p38 MAPK; norBNI; dorsal hippocampus

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