Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1.
Accumulating evidence suggests that spinal astrocytes play an important role in the genesis of persistent pain, by increasing the activity of spinal cord nociceptive neurons, i.e., central sensitization. However, direct evidence of whether activation of astrocytes is sufficient to induce chronic pain symptoms is lacking. We investigated whether and how spinal injection of activated astrocytes could produce mechanical allodynia, a cardinal feature of chronic pain, in naïve mice. Spinal (intrathecal) injection of astrocytes, which were prepared from cerebral cortexes of neonatal mice and briefly stimulated by tumor necrosis factor-alpha (TNF-α), induced a substantial decrease in paw withdrawal thresholds, indicating the development of mechanical allodynia. This allodynia was prevented when the astrocyte cultures were pretreated with a peptide inhibitor of c-Jun N-terminal kinase (JNK), D-JNKI-1. Of note a short exposure of astrocytes to TNF-α for 15 min dramatically increased the expression and release of the chemokine monocyte chemoattractant protein-1 (MCP-1), even 3 h after TNF-α withdrawal, in a JNK-dependent manner. In parallel, intrathecal administration of TNF-α induced MCP-1 expression in spinal cord astrocytes. In particular, mechanical allodynia induced by TNF-α-activated astrocytes was reversed by a MCP-1 neutralizing antibody. Finally, pretreatment of astrocytes with MCP-1 siRNA attenuated astrocytes-induced mechanical allodynia. Taken together, our results suggest that activated astrocytes are sufficient to produce persistent pain symptom in naïve mice by releasing MCP-1.
Gao
Yong-Jing
YJ
Sensory Plasticity Laboratory, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Pain Research Center, Boston, Massachusetts 02115, USA. yjing@zeus.bwh.harvard.edu
Zhang
Ling
L
Ji
Ru-Rong
RR
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D007278:Injections, Spinal / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D017288:Pain Threshold / Q000187:drug effects; D034741:RNA, Small Interfering / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D013116:Spinal Cord / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*
C491049:Aif1 protein, mouse; D000906:Antibodies; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C469948:Tnfrh2 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4