The transition from acute to chronic pain is likely to result from a complex combination of mechanisms. It is important to develop a useful preclinical animal model that can replicate the complexity of the human condition. Previous studies have shown that psychosocial and socio-environmental factors are involved in the development of chronic postsurgical pain. In our preliminary studies, we found that forced swim stress significantly enhances plantar incision-induced ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation and greatly prolongs plantar incision-induced pain, but forced swim stress alone does not produce pain behaviors;we also found that targeted mutation of AMPA receptor GluA1 phosphorylation site Ser831 significantly inhibits stress-induced prolongation of incisional pain. Thus, stress may induce pain transition by regulating AMPA receptor phosphorylation. Recently, we further found that forced swim stress significantly increases GluA1 membrane surface expression and GluA2 internalization and thereby enhances synaptic AMPA receptor switch from Ca2+-impermeable (GluA2-containing) to Ca2+-permeable (GluA2-lacking) in the spinal dorsal horn neurons. This switch will increase Ca2+ influx and further activate Ca2+-dependent protein kinases, thereby promoting AMPA receptor phosphorylation and other phosphorylation-triggered activities. This positive feedback loop may contribute to the molecular mechanisms that underlie stress- induced pain transition. Therefore, we hypothesize that regulation of AMPA receptor phosphorylation and phosphorylation-triggered synaptic AMPA receptor switch from Ca2+-impermeable to Ca2+-permeable contribute to a key mechanism by which stress induces the transition from acute to chronic pain. To address this central hypothesis, pain scientists from Dr. Tao's laboratory and non-pain neuroscientists with expertise in neuroplasticity from Dr. Huganir's laboratory will work together. We will combine plantar incision with different levels of forced swim stress to develop a new animal model to study pain transition (specific aim 1), we will investigate stress-produced regulation of AMPA receptor activities (phosphorylation, trafficking, synaptic targeting, and subunit composition change) in our pain transition model (specific aim 2), and we will investigate the role of phosphorylation-triggered switch of AMPA receptors from Ca2+-impermeable to Ca2+- permeable in stress-induced pain transition (specific aim 3). The overall goal of this proposal is to develop a new animal model to study pain transition and provide critical evidence to characterize the pain transition model. The proposed studies will demonstrate the role of stress-produced AMPA receptor regulation in the transition from acute to chronic pain and shed new light on the pathogenesis of chronic postsurgical pain.

Public Health Relevance

This project is focused on the development of a new animal model to study pain transition. Our hypothesis is that regulation of AMPA receptor phosphorylation and phosphorylation-triggered synaptic AMPA receptor switch from Ca2+-impermeable to Ca2+-permeable contribute to a key mechanism by which stress induces the transition from acute to chronic pain. The proposed studies will demonstrate the role of stress-produced AMPA receptor regulation in stress-induced pain transition and shed new light on the pathogenesis of chronic postsurgical pain.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE022880-03
Application #
8681422
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Li, Changsheng; Yang, Ya; Liu, Sufang et al. (2014) Stress induces pain transition by potentiation of AMPA receptor phosphorylation. J Neurosci 34:13737-46
Liu, Sufang; Li, Changsheng; Xing, Ying et al. (2014) Effect of transplantation of human embryonic stem cell-derived neural progenitor cells on adult neurogenesis in aged hippocampus. Am J Stem Cells 3:21-6
Liu, Sufang; Li, Changsheng; Xing, Ying et al. (2014) Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain. Neural Regen Res 9:458-9
Li, Changsheng; Liu, Sufang; Xing, Ying et al. (2014) The role of hippocampal tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 mice. Anesth Analg 119:413-9
Tao, Feng; Li, Qun; Liu, Su et al. (2013) Role of neuregulin-1/ErbB signaling in stem cell therapy for spinal cord injury-induced chronic neuropathic pain. Stem Cells 31:83-91