Switching of delta opioid receptor subtypes in central amygdala microcircuits is associated with anxiety states in pain

Wenjie Zhou,Yanhua Li,Xiaojing Meng,An Liu,Yu Mao,Xia Zhu,Qian Meng,Yan Jin,Zhi Zhang,Wenjuan Tao

doi:10.1016/j.jbc.2021.100277

Abstract

Anxiety is often comorbid with pain. Delta opioid receptors (DORs) are promising targets for the treatment of pain and mental disorders with little addictive potential. However, their roles in anxiety symptoms at different stages of pain are unclear. In the current study, mice with inflammatory pain at the fourth hour following complete Freund’s adjuvant (CFA) injection displayed significant anxiety-like behavior, which disappeared at the seventh day. Combining electrophysiology, optogenetics, and pharmacology, we found that activation of delta opioid receptor 1 (DOR1) in the central nucleus amygdala (CeA) inhibited both the anxiolytic excitatory input from the basolateral amygdala (BLA) and the anxiogenic excitatory input from the parabrachial nucleus (PBN). In contrast, activation of delta opioid receptor 2 (DOR2) did not affect CeA excitatory synaptic transmission in normal and 4-h CFA mice but inhibited the excitatory projection from the PBN rather than the BLA in 7-day CFA mice. Furthermore, the function of both DOR1 and DOR2 was downregulated to the point of not being detectable in the CeA of mice at the 21st day following CFA injection. Taken together, these results suggest that functional switching of DOR1 and DOR2 is associated with anxiety states at different stages of pain via modulating the activity of specific pathways (BLA-CeA and PBN-CeA).

Highlights

Pain is a complex disorder including an unpleasant sensory and emotional experience
Anxiety-like behaviors of the mice treated with complete Freund’s adjuvant (CFA) for 4 h (CFA 4 h) or 7 days (CFA 7 days) were separately assessed by the elevated plus maze (EPM) test and open field test (OFT)
The CFA 4 h mice displayed anxiety-like behaviors, indicated by less time spent in and fewer entries into the open arms of the EPM or central area of the open field compared with the saline 4-h mice (Fig. 1, B–E), but no significant difference was detected between saline 7-day (Sal 7 days) and CFA 7-day mice (Fig. 1, F–I)

Summary

Introduction

Pain is a complex disorder including an unpleasant sensory and emotional experience. Pain is closely associated with a number of physiological and psychological maladaptations, including anxiety [1, 2], which may lead to an excessive duration and intensity of pain [3]. Opioid receptors belong to the G-protein-coupled receptors, which have three subtypes: the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor [5] Both the analgesic and rewarding effects of opioid drugs are primarily mediated by MORs [6]. A recent study found that both DOR1 and DOR2 coexist in the same neurons and produce the opposite responses [18] These data suggest that the two DOR subtypes in the central nervous system may have different functions. The function of different subtypes of DORs in the CeA for pain-associated anxiety is not clear. We aimed to characterize the role of the two DOR subtypes (DOR1 and DOR2) in the CeA for pain-associated anxiety. Switching of DOR subtypes for pain-induced anxiety at different stages of pain in a mouse model that was established by complete Freund’s adjuvant (CFA)

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Conclusion