Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation

Xu-Hui Li; Takanori Matsuura; Man Xue; Qi-Yu Chen; Ren-Hao Liu; Jing-Shan Lu; Wantong Shi; Kexin Fan; Zhaoxiang Zhou; Zhuang Miao; Jiale Yang; Sara Wei; Feng Wei; Tao Chen; Min Zhuo

doi:10.1016/j.celrep.2021.109411

Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation

Cell Rep. 2021 Jul 20;36(3):109411. doi: 10.1016/j.celrep.2021.109411.

Authors

Xu-Hui Li¹, Takanori Matsuura², Man Xue³, Qi-Yu Chen⁴, Ren-Hao Liu³, Jing-Shan Lu⁴, Wantong Shi³, Kexin Fan³, Zhaoxiang Zhou³, Zhuang Miao⁵, Jiale Yang⁶, Sara Wei⁶, Feng Wei⁶, Tao Chen⁷, Min Zhuo⁸

Affiliations

¹ Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China.
² Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Orthopaedics, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
³ Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
⁴ Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China.
⁵ Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁶ Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD 20201, USA.
⁷ Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Department of Anatomy, Histology, Embryology & K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710032, China.
⁸ Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Institute of Brain Research, Qingdao International Academician Park, Qingdao, Shandong, China. Electronic address: min.zhuo@utoronto.ca.

PMID: 34289348
DOI: 10.1016/j.celrep.2021.109411

Abstract

Oxytocin is a well-known neurohypophysial hormone that plays an important role in behavioral anxiety and nociception. Two major forms of long-term potentiation, presynaptic LTP (pre-LTP) and postsynaptic LTP (post-LTP), have been characterized in the anterior cingulate cortex (ACC). Both pre-LTP and post-LTP contribute to chronic-pain-related anxiety and behavioral sensitization. The roles of oxytocin in the ACC have not been studied. Here, we find that microinjections of oxytocin into the ACC attenuate nociceptive responses and anxiety-like behavioral responses in animals with neuropathic pain. Application of oxytocin selectively blocks the maintenance of pre-LTP but not post-LTP. In addition, oxytocin enhances inhibitory transmission and excites ACC interneurons. Similar results are obtained by using selective optical stimulation of oxytocin-containing projecting terminals in the ACC in animals with neuropathic pain. Our results demonstrate that oxytocin acts on central synapses and reduces chronic-pain-induced anxiety by reducing pre-LTP.

Keywords: anterior cingulate cortex; anxiety; inhibitory transmission; long-term potentiation; neuropathic pain; oxytocin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / pharmacology
Animals
Anti-Anxiety Agents / pharmacology
Anxiety / physiopathology*
Behavior, Animal / drug effects
Calcium / metabolism
Chronic Pain / pathology
Chronic Pain / physiopathology
Emotions* / drug effects
Female
Gyrus Cinguli / drug effects
Gyrus Cinguli / pathology*
Gyrus Cinguli / physiopathology
Interneurons / drug effects
Light
Long-Term Potentiation* / drug effects
Male
Mice
Mice, Inbred C57BL
Microinjections
Nerve Tissue / drug effects
Nerve Tissue / pathology
Nerve Tissue / physiopathology
Neural Inhibition / drug effects
Neuralgia / complications
Neuralgia / pathology*
Neuralgia / physiopathology*
Oxytocin / administration & dosage
Oxytocin / pharmacology*
Paraventricular Hypothalamic Nucleus / drug effects
Paraventricular Hypothalamic Nucleus / pathology
Paraventricular Hypothalamic Nucleus / physiopathology
Presynaptic Terminals / drug effects
Presynaptic Terminals / pathology*
Receptors, G-Protein-Coupled / metabolism
Receptors, GABA-A / metabolism
Receptors, Oxytocin / genetics
Receptors, Oxytocin / metabolism
Signal Transduction / drug effects
Synaptic Transmission / drug effects
Up-Regulation / drug effects

Substances

Analgesics
Anti-Anxiety Agents
Receptors, G-Protein-Coupled
Receptors, GABA-A
Receptors, Oxytocin
Oxytocin
Calcium

Grants and funding

PJT-148648/CIHR/Canada