title: Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia.
abstract: Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting saltatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e., mechanical allodynia). Our earlier (Liu et al., 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84-104) into an intact sciatic nerve produces a robust and long-lasting (>30days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel α2δ1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function-blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Eddinger
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
authors.forename: Mila
authors.initials: M
authors.lastname: Angert
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dolkas
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA. Electronic address: vshubayev@ucsd.edu.
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Shubayev
mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D000077206:Gabapentin; D023281:Genomics; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D020910:Ketorolac / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D016861:Cyclooxygenase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D015850:Interleukin-6; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D061567:Voltage-Gated Sodium Channel Blockers; C094241:myelin basic protein 84-104; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016291:Dizocilpine Maleate; D008012:Lidocaine; D020910:Ketorolac
keywords: Adaptive immunity; Allodynia; Autoimmunity and pain; Cacna2d1; Chronic pain; Female pain; Gabapentin; Interferon; Interleukin 6; MBP; Mechanical hypersensitivity; Myelin; Myelin basic protein; Neuropathic pain; Nude rat; T cells