We propose that pathological pain from innocuous mechanical stimulation such as light touch or slight air movement (defined as mechanical allodynia) represents an autoimmune disorder in females. This conceptually new view of this refractory chronic pain phenotype is the overarching thesis of our renewal application. Recent seminal work implicates adaptive immune/T cells and innate immune system/microglia in the development of mechanical allodynia in female and male rodents, respectively. However, the mechanisms of this sexual dimorphism phenomenon are obscure. Our groundbreaking data suggests that a known auto-antigen, myelin basic protein (MBP), holds the mechanistic key to sexual dimorphism in mechanical allodynia. We suggest that any, including physical, damage to myelin sheath on mechanosensitive A?-afferent fibers results in proteolytic liberation of cryptic MBP peptides normally sheltered from immunosurveillance. The peptide encoding the central (84-104) region of MBP (MBP84-104) produces direct, robust and lasting hypersensitivity to light touch (A? fiber-mediated) but not thermal (C fiber-mediated) stimulation. The conserved histidine (H)-89 site is required to intracellular transport and the algesic activity of MBP84-104. Using biochemical and molecular tools, including mass-spectrometry, RNA-sequencing, bioinformatics, structural modeling, and immunocapture of wildtype, mutant and control peptides, combined with rigorous pharmacological, neuropathological, and behavioral analyses, we identified a cluster of the MBP84-104 interactors and downstream signaling factors promoting in females (and/or protecting males from) the development of allodynia. These MBP84-104-related leads with the established roles in pain circuitry, such as the X-chromosome imprinted gene interleukin 6, are here linked to a master-regulator of lipid, immune and estrogen receptor signaling pathways, liver X receptor, which is new to the pain field. With our unique, accrued toolset and rigorous data obtained in a prolific collaboration among the teams of the PI, Veronica Shubayev (UCSD) with Tony Yaksh (UCSD) and Alex Strongin (SBP), we aim to identify the precise molecular events in nerve, dorsal root ganglia and spinal cord leading to the sexual dimorphism in neuropathic pain. We expect our innovative findings will foster the development of conceptually novel analgesic therapeutics useful in refractory types of chronic pain.
Injury of sensory nerves may result in a devastating state of neuropathic pain, resistant to standard analgesics. This program will identify the fundamentally new molecular events of the abnormal immune response to nerve injury that result in neuropathic pain. Specific focus is on the mechanism distinct in female and male rodents and related to the insulating sheath enwrapping neurons (called myelin).
|Remacle, Albert G; Dolkas, Jennifer; Angert, Mila et al. (2018) A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples. J Immunol Methods 455:80-87|
|Shubayev, Veronica I; Strongin, Alex Y; Yaksh, Tony L (2018) Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome. Mol Pain 14:1744806918815005|
|Chernov, Andrei V; Remacle, Albert G; Hullugundi, Swathi K et al. (2018) Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain. FEBS J 285:3485-3502|
|Remacle, Albert G; Hullugundi, Swathi K; Dolkas, Jennifer et al. (2018) Acute- and late-phase matrix metalloproteinase (MMP)-9 activity is comparable in female and male rats after peripheral nerve injury. J Neuroinflammation 15:89|
|Cieplak, Piotr; Strongin, Alex Y (2017) Matrix metalloproteinases - From the cleavage data to the prediction tools and beyond. Biochim Biophys Acta Mol Cell Res 1864:1952-1963|
|Hong, Sanghyun; Remacle, Albert G; Shiryaev, Sergei A et al. (2017) Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain. Brain Behav Immun 60:282-292|
|Remacle, Albert G; Cieplak, Piotr; Nam, Dong Hyun et al. (2017) Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis. Oncotarget 8:2781-2799|
|Ko, Justin S; Eddinger, Kelly A; Angert, Mila et al. (2016) Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia. Brain Behav Immun 56:378-89|
|Liu, Huaqing; Dolkas, Jennifer; Hoang, Khan et al. (2015) The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury. J Neuroinflammation 12:158|
|Remacle, Albert G; Kumar, Sonu; Motamedchaboki, Khatereh et al. (2015) Matrix Metalloproteinase (MMP) Proteolysis of the Extracellular Loop of Voltage-gated Sodium Channels and Potential Alterations in Pain Signaling. J Biol Chem 290:22939-44|
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