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).
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