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• W3034882257 abstract "In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP(84-104)) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP(84-104) via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-seq and systems biology analysis revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP(84-104) induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP(84-104). According to sustained sensitization in tiers 1 and 2, T cell–related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP(84-104)–induced pain is T cell–dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multisite, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP(84-104) acts through sustained co-activation of metabolic, estrogen receptor–mediated nociceptive, and autoimmune signaling programs. In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP(84-104)) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP(84-104) via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-seq and systems biology analysis revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP(84-104) induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP(84-104). According to sustained sensitization in tiers 1 and 2, T cell–related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP(84-104)–induced pain is T cell–dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multisite, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP(84-104) acts through sustained co-activation of metabolic, estrogen receptor–mediated nociceptive, and autoimmune signaling programs. Chronic pain is a major public health problem worldwide (1Treede R.D. Jensen T.S. Campbell J.N. Cruccu G. Dostrovsky J.O. Griffin J.W. Hansson P. Hughes R. Nurmikko T. Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes.Neurology. 2008; 70 (18003941): 1630-163510.1212/01.wnl.0000282763.29778.59Crossref PubMed Scopus (1885) Google Scholar, 2Nahin R.L. Estimates of pain prevalence and severity in adults: United States, 2012.J. Pain. 2015; 16 (26028573): 769-78010.1016/j.jpain.2015.05.002Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar, 3Price T.J. Basbaum A.I. Bresnahan J. Chambers J.F. De Koninck Y. Edwards R.R. Ji R.R. Katz J. Kavelaars A. Levine J.D. Porter L. Schechter N. Sluka K.A. Terman G.W. Wager T.D. et al.Transition to chronic pain: opportunities for novel therapeutics.Nat. Rev. Neurosci. 2018; 19: 383-38410.1038/s41583-018-0012-5Crossref PubMed Scopus (44) Google Scholar). 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McMurray S. McMahon S.B. Denk F. Sex differences in peripheral not central immune responses to pain-inducing injury.Sci. Rep. 2017; 7 (29184144): 1646010.1038/s41598-017-16664-zCrossref PubMed Scopus (54) Google Scholar, 13Stephens K.E. Chen Z. Sivanesan E. Raja S.N. Linderoth B. Taverna S.D. Guan Y. RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation.Mol. Pain. 2018; 14 (1744806918817429, 30451078)10.1177/1744806918817429Crossref PubMed Scopus (17) Google Scholar, 14Stokes J.A. Cheung J. Eddinger K. Corr M. Yaksh T.L. Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.J. Neuroinflammation. 2013; 10 (24321498): 14810.1186/1742-2094-10-148Crossref PubMed Scopus (75) Google Scholar). Focal peripheral nerve injury produces pain in response to innocuous tactile stimulation (mechano-allodynia) in part through the activity of hematogenous T cells recruited from systemic circulation (15Moalem G. Xu K. Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats.Neuroscience. 2004; 129 (15541898): 767-77710.1016/j.neuroscience.2004.08.035Crossref PubMed Scopus (201) Google Scholar, 16Kleinschnitz C. Hofstetter H.H. Meuth S.G. Braeuninger S. Sommer C. Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression.Exp. Neurol. 2006; 200 (16674943): 480-48510.1016/j.expneurol.2006.03.014Crossref PubMed Scopus (105) Google Scholar, 17Costigan M. Moss A. Latremoliere A. Johnston C. Verma-Gandhu M. Herbert T.A. Barrett L. Brenner G.J. Vardeh D. Woolf C.J. Fitzgerald M. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity.J. Neurosci. 2009; 29 (19923276): 14415-1442210.1523/JNEUROSCI.4569-09.2009Crossref PubMed Scopus (267) Google Scholar, 18Draleau K. Maddula S. Slaiby A. Nutile-McMenemy N. De Leo J. Cao L. Phenotypic identification of spinal cord-infiltrating CD4 T lymphocytes in a murine model of neuropathic pain.J. Pain Relief. 2014; 3 (003) (25143871)10.4172/2167-0846.S3-003PubMed Google Scholar). Seminal research implicated T cell activity in selective mediation of mechano-allodynia in female, but not male, mice with peripheral nerve trauma, as males employed innate immune spinal microglia activity (11Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. Yang M. Shi X.Q. Huang H. Pillon N.J. Bilan P.J. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18 (26120961): 1081-108310.1038/nn.4053Crossref PubMed Scopus (570) Google Scholar, 19Rosen S.F. Ham B. Drouin S. Boachie N. Chabot-Dore A.J. Austin J.S. Diatchenko L. Mogil J.S. T-cell mediation of pregnancy analgesia affecting chronic pain in mice.J. Neurosci. 2017; 37 (28877966): 9819-982710.1523/JNEUROSCI.2053-17.2017Crossref PubMed Scopus (24) Google Scholar). The mechanisms and the specific T cell epitopes released that underlie the female-specific T cell activity in mechano-allodynia remain obscure. Mechanosensory dorsal root ganglia (DRG) neurons of the leg (sciatic nerve) are among the longest cells in the body, spanning from foot to spine. Their lipid-rich, multilamellar myelin membrane sheath provides electrical and metabolic insulation and ensures fast, saltatory conduction of a tactile-stimulated impulse (20Taveggia C. Feltri M.L. Wrabetz L. Signals to promote myelin formation and repair.Nat. Rev. Neurol. 2010; 6 (20404842): 276-28710.1038/nrneurol.2010.37Crossref PubMed Scopus (202) Google Scholar). In healthy nerves, myelin compaction and integrity are maintained via interactions of the intrinsically unstructured, cationic myelin basic protein (MBP) with the anionic membrane phospholipids (21Boggs J.M. Myelin basic protein: a multifunctional protein.Cell Mol. Life Sci. 2006; 63 (16794783): 1945-196110.1007/s00018-006-6094-7Crossref PubMed Scopus (349) Google Scholar, 22Harauz G. Ladizhansky V. Boggs J.M. Structural polymorphism and multifunctionality of myelin basic protein.Biochemistry. 2009; 48 (19642704): 8094-810410.1021/bi901005fCrossref PubMed Scopus (140) Google Scholar), including phosphatidylinositol 4,5-bisphosphate (PIP2) (23Nawaz S. Kippert A. Saab A.S. Werner H.B. Lang T. Nave K.A. Simons M. Phosphatidylinositol 4,5-bisphosphate-dependent interaction of myelin basic protein with the plasma membrane in oligodendroglial cells and its rapid perturbation by elevated calcium.J. Neurosci. 2009; 29 (19369548): 4794-480710.1523/JNEUROSCI.3955-08.2009Crossref PubMed Scopus (69) Google Scholar). Disruption of structural and molecular integrity of myelin by peripheral nerve trauma contributes to mechano-allodynia (24Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain.Exp. Brain Res. 2009; 196 (19242687): 115-12810.1007/s00221-009-1724-6Crossref PubMed Scopus (238) Google Scholar, 25Henry M.A. Luo S. Foley B.D. Rzasa R.S. Johnson L.R. Levinson S.R. Sodium channel expression and localization at demyelinated sites in painful human dental pulp.J. Pain. 2009; 10 (19559391): 750-75810.1016/j.jpain.2009.01.264Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 26Kobayashi H. Chattopadhyay S. Kato K. Dolkas J. Kikuchi S. Myers R.R. Shubayev V.I. MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.Mol. Cell. Neurosci. 2008; 39 (18817874): 619-62710.1016/j.mcn.2008.08.008Crossref PubMed Scopus (86) Google Scholar). MBP is a putative autoantigen implicated in the pathogenesis of autoimmune demyelinating states of the central (21Boggs J.M. Myelin basic protein: a multifunctional protein.Cell Mol. Life Sci. 2006; 63 (16794783): 1945-196110.1007/s00018-006-6094-7Crossref PubMed Scopus (349) Google Scholar, 22Harauz G. Ladizhansky V. Boggs J.M. Structural polymorphism and multifunctionality of myelin basic protein.Biochemistry. 2009; 48 (19642704): 8094-810410.1021/bi901005fCrossref PubMed Scopus (140) Google Scholar) and peripheral (27Kadlubowski M. Hughes R.A. Identification of the neuritogen for experimental allergic neuritis.Nature. 1979; 277 (310522): 140-14110.1038/277140a0Crossref PubMed Scopus (174) Google Scholar) nervous systems. In female rats with peripheral nerve trauma, we have shown that inhibition of matrix metalloproteinase-mediated proteolysis of MBP attenuates mechano-allodynia at least in part by blocking the release of T cell epitopes of MBP and T cell homing into the nerve (26Kobayashi H. Chattopadhyay S. Kato K. Dolkas J. Kikuchi S. Myers R.R. Shubayev V.I. MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.Mol. Cell. Neurosci. 2008; 39 (18817874): 619-62710.1016/j.mcn.2008.08.008Crossref PubMed Scopus (86) Google Scholar, 28Hong S. Remacle A.G. Shiryaev S.A. Choi W. Hullugundi S.K. Dolkas J. Angert M. Nishihara T. Yaksh T.L. Strongin A.Y. Shubayev V.I. Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.Brain Behav. Immun. 2017; 60 (27833045): 282-29210.1016/j.bbi.2016.11.003Crossref PubMed Scopus (11) Google Scholar, 29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar). Specifically, focal nerve trauma causes release of the immunodominant T cell epitope of MBP comprising the evolutionarily conserved, invariant α-helix 87VVHFF91 motif (26Kobayashi H. Chattopadhyay S. Kato K. Dolkas J. Kikuchi S. Myers R.R. Shubayev V.I. MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.Mol. Cell. Neurosci. 2008; 39 (18817874): 619-62710.1016/j.mcn.2008.08.008Crossref PubMed Scopus (86) Google Scholar, 28Hong S. Remacle A.G. Shiryaev S.A. Choi W. Hullugundi S.K. Dolkas J. Angert M. Nishihara T. Yaksh T.L. Strongin A.Y. Shubayev V.I. Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.Brain Behav. Immun. 2017; 60 (27833045): 282-29210.1016/j.bbi.2016.11.003Crossref PubMed Scopus (11) Google Scholar, 29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar, 31Remacle A.G. Dolkas J. Angert M. Hullugundi S.K. Chernov A.V. Jones 3rd, R.C.W. Shubayev V.I. Strongin A.Y. A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples.J. Immunol. Methods. 2018; 455 (29428829): 80-8710.1016/j.jim.2018.02.002Crossref PubMed Scopus (3) Google Scholar). To elucidate the downstream events of the MBP peptide exposure in mechano-allodynia, we identified the 84-104 fragment of MBP (MBP(84-104)) as the potent pro-algesic peptide in female rats (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar). In female rats, endoneurial delivery of the pure MBP(84-104), but not the control scramble, peptide by an adjuvant-free injection into an intact sciatic nerve (IS) induces persistent (2 weeks) mechano-allodynia (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar, 32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016; 56 (26970355): 378-38910.1016/j.bbi.2016.03.003Crossref PubMed Scopus (20) Google Scholar). The MBP(84-104)-induced mechano-allodynia in females is refractory to systemically delivered analgesics, such as ketorolac and lidocaine (32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016; 56 (26970355): 378-38910.1016/j.bbi.2016.03.003Crossref PubMed Scopus (20) Google Scholar). The IS MBP(84-104) mechano-allodynia is T cell-dependent, as shown using athymic nude female rats lacking mature T cells (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar) and by mutagenesis of the T cell-binding site of the peptide (30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar). In contrast to a focal nerve trauma, IS MBP(84-104) is not accompanied by major neuropathological changes (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar), making it an attractive model to study sustained mechano-allodynia, without background effects of acute degenerative and reparative processes caused by nerve trauma. Based on these data obtained in female rats, we have proposed that the autoimmune pathogenesis of mechano-allodynia arises due to MBP(84-104)/T cell-mediated targeting of myelinated afferents (28Hong S. Remacle A.G. Shiryaev S.A. Choi W. Hullugundi S.K. Dolkas J. Angert M. Nishihara T. Yaksh T.L. Strongin A.Y. Shubayev V.I. Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.Brain Behav. Immun. 2017; 60 (27833045): 282-29210.1016/j.bbi.2016.11.003Crossref PubMed Scopus (11) Google Scholar, 29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar, 31Remacle A.G. Dolkas J. Angert M. Hullugundi S.K. Chernov A.V. Jones 3rd, R.C.W. Shubayev V.I. Strongin A.Y. A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples.J. Immunol. Methods. 2018; 455 (29428829): 80-8710.1016/j.jim.2018.02.002Crossref PubMed Scopus (3) Google Scholar, 32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016; 56 (26970355): 378-38910.1016/j.bbi.2016.03.003Crossref PubMed Scopus (20) Google Scholar, 33Shubayev V.I. Strongin A.Y. Yaksh T.L. Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome.Mol. Pain. 2018; 14 (1744806918815005, 30392459)10.1177/1744806918815005Crossref PubMed Scopus (3) Google Scholar, 34Remacle A.G. Hullugundi S.K. Dolkas J. Angert M. Cieplak P. Scott D. Chernov A.V. Shubayev V.I. Strongin A.Y. Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism.Biochem. J. 2018; 475 (29954845): 2355-237610.1042/BCJ20180137Crossref PubMed Scopus (1) Google Scholar, 35Shubayev V.I. Strongin A.Y. Yaksh T.L. Role of myelin auto-antigens in pain: a female connection.Neural Regen. Res. 2016; 11 (27482203): 890-89110.4103/1673-5374.184452PubMed Google Scholar). To determine the role of MBP(84-104) as an epitope initiating the sexual dimorphism (female specificity) of T cell action in mechano-allodynia in mice (11Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. Yang M. Shi X.Q. Huang H. Pillon N.J. Bilan P.J. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18 (26120961): 1081-108310.1038/nn.4053Crossref PubMed Scopus (570) Google Scholar), we here comparatively assessed mechanical sensitivity after IS MBP(84-104) in female and male mice. Our comprehensive, comparative, genome-wide transcriptomic analysis revealed molecular signatures in the injected nerve and ipsilateral DRG and spinal cord, with biological processes and signaling cascades under MBP(84-104) control. The present data provide the first evidence that nerve MBP(84-104) exposure is sufficient to induce mechano-allodynia in a sexually dimorphic (female-specific) manner. We here reveal an overarching 3-tier signaling program associated with sex-specific pain mediation and establish a comprehensive, open-access database for future data mining of the mechanisms leading to autoimmune mediation of neuropathic pain, specifically in females. Release of MBP(84-104) drives T cell-dependent mechano-allodynia after focal nerve injury in female rodents (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar, 32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016; 56 (26970355): 378-38910.1016/j.bbi.2016.03.003Crossref PubMed Scopus (20) Google Scholar). Whether a comparable process exists in male rodents is not known. The recent evidence of female-specific T cell mediation of mechano-allodynia signaling in C57BL6 mice (11Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. Yang M. Shi X.Q. Huang H. Pillon N.J. Bilan P.J. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18 (26120961): 1081-108310.1038/nn.4053Crossref PubMed Scopus (570) Google Scholar, 19Rosen S.F. Ham B. Drouin S. Boachie N. Chabot-Dore A.J. Austin J.S. Diatchenko L. Mogil J.S. T-cell mediation of pregnancy analgesia affecting chronic pain in mice.J. Neurosci. 2017; 37 (28877966): 9819-982710.1523/JNEUROSCI.2053-17.2017Crossref PubMed Scopus (24) Google Scholar) prompted us to test the algesic effect of MBP(84-104) in female versus male C57BL6 mice. Withdrawal thresholds to mechanical stimulation by von Frey filaments were measured in mice that received a single adjuvant-free IS bolus injection of pure MBP(84-104) or scramble (MBPS) peptides, both diluted in PBS (30 μg in 3 μl, each, Fig. 1a). PBS vehicle injections (3 µl) served as control. In agreement with our prior reports in female rats (29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 30Chernov A.V. Remacle A.G. Hullugundi S.K. Cieplak P. Angert M. Dolkas J. Shubayev V.I. Strongin A.Y. 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. 2018; 285 (30079618): 3485-350210.1111/febs.14623Crossref PubMed Scopus (2) Google Scholar, 32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016; 56 (26970355): 378-38910.1016/j.bbi.2016.03.003Crossref PubMed Scopus (20) Google Scholar), female mice displayed a highly significant reduction in the mechanical force required to evoke hind paw withdrawal (i.e. mechano-allodynia) after IS MBP(84-104), but not PBS or MBPS. The allodynia persisted over the 7-day testing period (Fig. 1b). In contrast, male mice after IS MBP(84-104) exhibited mechanical thresholds comparable with control MBPS and PBS injection over the 7-day assessment (Fig. 1c). No delayed mechanical sensitivity was observed in males over additional testing out to 24 days (data not shown). No hypersensitivity was observed in contralateral paws in either sex (data not shown). We conclude that MBP(84-104) mediates mechano-allodynia selectively in female, but not male, mice. Global genome-wide expression profiling is used to elucidate precise molecular signatures of pain (12Lopes D.M. Malek N. Edye M. Jager S.B. McMurray S. McMahon S.B. Denk F. Sex differences in peripheral not central immune responses to pain-inducing injury.Sci. Rep. 2017; 7 (29184144): 1646010.1038/s41598-017-16664-zCrossref PubMed Scopus (54) Google Scholar, 29Liu H. Shiryaev S.A. Chernov A.V. Kim Y. Shubayev I. Remacle A.G. Baranovskaya S. Golubkov V.S. Strongin A.Y. Shubayev V.I. Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.J. Neuroinflammation. 2012; 9: 11910.1186/1742-2094-9-119Crossref PubMed Scopus (38) Google Scholar, 32Ko J.S. Eddinger K.A. Angert M. Chernov A.V. Dolkas J. Strongin A.Y. Yaksh T.L. Shubayev V.I. Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.Brain Behav. Immun. 2016;" @default.
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• W3034882257 title "A myelin basic protein fragment induces sexually dimorphic transcriptome signatures of neuropathic pain in mice" @default.
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