Through long-term research, the team, led by Professor Zhuo Min of the Frontier Institute of Science and Technology of Xi'an Jiaotong University (XJTU), has found ways to reduce anxiety in animals with chronic pain.

They found that chronic pain can cause changes in the synaptic plasticity of the cerebral cortex, which is closely related to the pain and anxiety behavior of chronic pain, and the long-term potentiation (LTP) of synaptic transmission in the anterior cingulate cortex (ACC), which is another important molecular mechanism of chronic pain.

In 2015, Zhuo's team published an article in Neuron which explained that the cortical synapses of adult mice have a presynaptic kainate receptor (KA receptor) that is not dependent on the NMDA receptor presynaptic LTP (Pre-LTP).

At the synaptic level, Pre-LTP enhances the presynaptic release of neurotransmitters, causing the sensitization of postsynaptic receptors. This enhanced synaptic transmission further leads to anxiety and the aggravation of pain sensation, and inhibits the expression of Pre-LTP, which can weaken the anxiety behavior of animals that suffer from chronic pain.

Oxytocin is a classic neuropituitary hormone. It is synthesized and released into the blood by neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and although it mainly promotes childbirth and breastfeeding, it also has an anti-anxiety and analgesic effect.

Many studies have shown that oxytocin can reduce people's anxiety, enhance social skills, and improve people's feelings of happiness, so it is also referred to as the "hormone of love".

Studies have shown that people with low levels of anxiety have higher levels of oxytocin in their cerebrospinal fluid and plasma. However, the mechanism of oxytocin to eliminate anxiety, or to relieve or treat chronic pain has been in a blind spot in terms of scientific research. In the central nervous system, oxytocin also acts as a neurotransmitter, but whether or not oxytocin regulates central synaptic plasticity is unclear.

Zhuo's team recently used genetically modified mice, optogenetics, electrophysiology, and pharmacology to study comprehensive technologies and found that oxytocin can selectively eliminate anxiety caused by chronic pain and anxiety-related Pre-LTP. This effect is very likely produced by exciting inhibitory neurons in the cerebral cortex.

Through the elevated plus maze (EPM) and open field test, it can clearly detect that the anxiety behavior of mice with chronic pain resulted from common peroneal nerve (CPN) ligation.

A microinjection of oxytocin in ACC can significantly reduce the anxiety caused by chronic pain. Further use of optogenetic methods to activate the release of endogenous oxytocin in ACC can also significantly reduce chronic pain-related anxiety behavior, while inhibition of the release of endogenous oxytocin has no significant effect on anxiety behavior. 

Electrophysiological studies have found that exogenous or endogenous oxytocin selectively inhibits the maintenance of ACC neurons' Pre-LTP, but has no effect on Post-LTP.

Oxytocin excites inhibitory interneurons to enhance inhibitory synaptic transmission, the effect of which is regulated by signaling pathways controlled by GABA_A receptors and G protein-coupled receptors.

In addition, in animals suffering from chronic pain, it was also found that the oxytocin concentration of PVN and the expression of the oxytocin receptor of ACC were significantly increased, indicating that the function of oxytocin was up-regulated after chronic pain.

This research has discovered a new anti-anxiety mechanism of oxytocin, that is, oxytocin produces an anxiolytic effect by inhibiting cortical Pre-LTP, and further proves that the Pre-LTP of the ACC plays an important role in anxiety caused by chronic pain. It also provides a new theoretical basis for future drug development and clinical treatments for anxiety.

The research results were published in Cell Reports, a sub-journal of Cell, with the title of Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation.

The first authors are post doctors Li Xuhui from the XJTU Frontier Institute of Science and Technology and Takanori Matsuur from the University of Toronto. The XJTU Frontier Institute of Science and Technology is the first author and corresponding author unit. Zhuo is the only corresponding author.

Doctoral students Xue Man, Chen Qiyu, Liu Renhao, Shi Wantong, Fan Kexin, Zhou Zhaoxiang and associate researcher Dr Lu Jingshan participated in this research.

This work is another important breakthrough of Zhuo's team in the field of chronic pain-related emotion research.

Chronic pain is a serious clinical disease. In addition to feeling pain, it can also cause negative emotions such as anxiety, depression, and fear, which in turn increases the pain of the patient, forming a vicious circle of pain, negative emotions and deep pain, which greatly damages the health of patients and increases the social and economic burden. It is understood that about 20 percent of the world's population suffers from the disease for an extended period of time.

Link to the paper: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00824-X

Introduction of Zhuo's team: http://fist.xjtu.edu.cn/cnd/index.htm