Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

Abstract

Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting salutatory 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, J. Neuroinflammation, 9 (1): 119, 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 (>30 days) 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.

Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain

“…A single H89G mutation was sufficient to significantly reduce the pain‐inducing efficacy of the peptide. Apart from the mechanical paw hypersensitivity behavior, the rats demonstrated no additional behavioral alterations, consistent with our previous data .…”

“…The algesic MBP84‐104 cryptic epitope is released in the nerve postinjury as a result of proteolysis of MBP. In our earlier studies, the injection of the main algesic, autoimmune MBP84‐104 epitope that is hidden in the native MBP fold, into an intact nerve was sufficient to induce robust, long‐lasting allodynia in rodents . Peptides representing MBP epitope region MBP80‐99 and MBP84‐104 exhibit a high level of amino acid conservation among evolutionary distant animal species (Fig.…”

“…RNA ‐seq data (Log 2 ( FPKM ) ≥ 0.01) were analyzed using Ingenuity IPA knowledgebase (Qiagen, version 2017) to predict the regulation of signaling pathways. RNA ‐seq data were compared to gene expression data from our previously published study in which MBP 84‐104 peptide was intrasciatically injected in female rats and the following 7 days specimens of ipsilateral sciatic nerves ( SN / MBP ), dorsal root ganglia ( DRG / MBP ), and dorsal spinal cord ( DSC / MBP ) were collected, pooled ( n = 6 per animal group), and total RNA s were profiled using gene expression microarrays ( GEO ID GSE34868). Color scales represent predictive activation (red) or inactivation (blue) of signaling pathways based on their z ‐scores.…”

“…cDNA was synthesized using a SuperScript first‐strand RT‐PCR kit (Invitrogen). Real‐time RT‐PCR was conducted using MX3005P qPCR System (Agilent) in 25‐μL reactions containing Taqman Universal PCR Master Mix (Ambion), cDNA (50 ng), specific forward and reverse primers (900 n m each), and Taqman probes (200–300 n m ) for Il‐6 and Atf3 mRNAs with a one‐step program: 95 °C, 10 min; 95 °C, 30 s; 60 °C, 1 min for 50 cycles. Duplicate samples without cDNA (a no template control) showed no contaminating DNA.…”

Etiology and Pharmacology of Neuropathic Pain

“…The initial inflammatory event at the site of nerve injury is a major trigger for the sequelae that lead to central sensitization (Watkins and Maier, 2002;Scholz and Woolf, 2007;White et al, 2007;Basbaum et al, 2009;Stemkowski and Smith, 2012b;Grace et al, 2014;Schuh et al, 2014;Ko et al, 2016) (Fig. 2A).…”