κ Opioid receptor activation in different brain regions differentially modulates anxiety-related behaviors in mice.
κ Opioid receptor system is widely implicated in the regulation of emotion. However, the findings about the role on anxiety in rodents are highly controversial, since both anxiogenic- and anxiolytic-like effects have been reported with κ opioid receptor activation. The mechanism and the underlying neuroanatomical substrates are unexplored. In the present study, we first investigated the effects of κ agonist U50,488H on anxiety-related behaviors over a wide range of doses, and we found that U50,488H produced dual effects in anxiety, with low dose being anxiogenic and high dose being anxiolytic. To assess the potential neuroanatomical substrates, we used phosphorylation of extracellular signal-related kinase1/2 (pERK1/2) to map the underlying neural circuits. We found that the anxiogenic effect of U50,488H was paralleled by an increase of pERK1/2 in the nucleus accumbens, whereas the anxiolytic effect was paralleled by an increase of pERK1/2 in the lateral septal nucleus. We then examined the behavioral consequences with locally microinjection of U50,488H, and we found that microinjection of U50,488H into the nucleus accumbens exerted anxiogenic-like effects, whereas microinjection of U50,488H into the lateral septal nucleus. Both effects can be abolished by κ antagonist nor-BNI pretreatment. To the best of our knowledge, the present work firstly provides the neuroanatomical sites that mediating the dual anxiogenic- and anxiolytic-like effects of U50,488H in mice. This study may help to explain current controversial role of κ receptor activation in anxiety-related behaviors in rodents, and may open new perspectives in the areas of anxiety disorders and κ receptor function.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Yu-Jun
YJ
Wang
Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai 201203, China; Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Ai
A
Hang
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Yu-Chen
YC
Lu
Department of Pharmacy, Dalian Medical University, Dalian 116044, China.
Yu
Y
Long
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Gui-Ying
GY
Zan
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Xue-Ping
XP
Li
Department of Pharmacy, Dalian Medical University, Dalian 116044, China.
Qian
Q
Wang
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Zeng-Xiang
ZX
Zhao
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Ling
L
He
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China.
Zhi-Qiang
ZQ
Chi
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai 201203, China. Electronic address: jgliu@mail.shcnc.ac.cn.
Jing-Gen
JG
Liu
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009292:Narcotic Antagonists / Q000008:administration & dosage; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
Anxiety; Dual effects; Region-specific; pERK1/2; κ Opioid receptor