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.
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.
|Tang, Yuanyuan; Liu, Sufang; Shu, Hui et al. (2018) AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain. Neuropharmacology 133:462-469|
|Liu, Sufang; Zhao, Zhiying; Guo, Yan et al. (2018) Spinal AMPA Receptor GluA1 Ser831 Phosphorylation Controls Chronic Alcohol Consumption-Produced Prolongation of Postsurgical Pain. Mol Neurobiol 55:4090-4097|
|Liu, Sufang; Li, Changsheng; Guo, Yan et al. (2018) PKM? Is Not Required for Development of Postsurgical Pain. Mol Neurobiol 55:2397-2402|
|Bai, Qian; Liu, Sufang; Shu, Hui et al. (2018) TNF? in the Trigeminal Nociceptive System Is Critical for Temporomandibular Joint Pain. Mol Neurobiol :|
|Liu, Sufang; Tang, Yuanyuan; Shu, Hui et al. (2018) Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model. Pain :|
|Liu, Sufang; Tao, Feng (2017) Role of ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor regulation in stress-induced pain chronification. World J Biol Chem 8:1-3|
|Li, Changsheng; Schaefer, Michele; Gray, Christy et al. (2017) Sensitivity to isoflurane anesthesia increases in autism spectrum disorder Shank3+/?cmutant mouse model. Neurotoxicol Teratol 60:69-74|
|Liu, Sufang; Tao, Feng (2016) Application of optogenetics-mediated motor cortex stimulation in the treatment of chronic neuropathic pain. J Transl Sci 2:286-288|
|Liu, Sufang; Li, Changsheng; Xing, Ying et al. (2016) Role of Neuromodulation and Optogenetic Manipulation in Pain Treatment. Curr Neuropharmacol 14:654-61|
|Mignogna, Maria Lidia; Giannandrea, Maila; Gurgone, Antonia et al. (2015) The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. Nat Commun 6:6504|
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