Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21.
Spinal cord injury (SCI) results in the generation and amplification of pain caused in part by injury-induced changes in neuronal excitability at multiple levels along the sensory neuraxis. We have previously shown that activated microglia, through an ERK (extracellular signal-regulated kinase)-regulated PGE(2) (prostaglandin E(2)) signaling mechanism, maintain neuronal hyperexcitability in the lumbar dorsal horn. Here, we examined whether microglial cells in the thalamus contribute to the modulation of chronic pain after SCI, and whether microglial activation is governed by spinally mediated increases in the microglial activator cysteine-cysteine chemokine ligand 21 (CCL21). We report that CCL21 is upregulated in dorsal horn neurons, that tissue levels are increased in the dorsal horn and ventral posterolateral (VPL) nucleus of the thalamus 4 weeks after SCI, and that the increase can be differentially reduced by spinal blockade at T1 or L1. In intact animals, electrical stimulation of the spinothalamic tract induces increases in thalamic CCL21 levels. Recombinant CCL21 injected into the VPL of intact animals transiently activates microglia and induces pain-related behaviors, effects that could be blocked with minocycline. After SCI, intra-VPL antibody-mediated neutralization of CCL21 decreases microglial activation and evoked hyperexcitability of VPL neurons, and restores nociceptive thresholds to near-normal levels. These data identify a novel pathway by which SCI triggers upregulation of the neuroimmune modulator CCL21 in the thalamus, which induces microglial activation in association with pain phenomena.
Zhao
Peng
P
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Waxman
Stephen G
SG
Hains
Bryan C
BC
D000818:Animals; D001522:Behavior, Animal; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects; D008297:Male; D017628:Microglia / Q000187:drug effects*; D010146:Pain / Q000209:etiology* / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D020651:Ventral Thalamic Nuclei / Q000378:metabolism / Q000473:pathology*
D054421:Chemokine CCL21; D019742:Chemokines, CC; D010751:Phosphopyruvate Hydratase
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