CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons.
Chemokines are important mediators in immune responses and inflammatory processes. Calcitonin gene-related peptide (CGRP) is produced in dorsal root ganglion (DRG) neurons. In this study, CGRP radioimmunoassay was used to investigate whether the chemokines CCL2 and CXCL1 could trigger CGRP release from cultured DRG neurons of neonatal rats and, if so, which cellular signaling pathway was involved. The results showed that CCL2 and CXCL1 ( approximately 5-100 ng/ml) evoked CGRP release and intracellular calcium elevation in a pertussis toxin (PTX)-sensitive manner. The CGRP release by CCL2 and CXCL1 was significantly inhibited by EGTA, omega-conotoxin GVIA (an N-type calcium channel blocker), thapsigargin, and ryanodine. Pretreatment of DRG neurons for 30 min with the inhibitors of phospholipase C (PLC) and protein kinase C (PKC) but not mitogen-activated protein kinases (MAPKs) significantly reduced CCL2- or CXCL1-induced CGRP release and intracellular calcium elevation. Intraplantar injection of CCL2 or CXCL1 produced hyperalgesia to thermal and mechanical stimulation in rats. These data suggest that CCL2 and CXCL1 can stimulate CGRP release and intracellular calcium elevation in DRG neurons. PLC-, PKC-, and calcium-induced calcium release from ryanodine-sensitive calcium stores signaling pathways are involved in CCL2- and CXCL1-induced CGRP release from primary nociceptive neurons, in which chemokines produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons.
Qin
Xiaomei
X
Institute of Vascular Medicine, Peking University Third Hospital, Beijing, People's Republic of China.
Wan
You
Y
Wang
Xian
X
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000276:immunology / Q000494:pharmacology*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000276:immunology / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000276:immunology / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D037342:Pertussis Toxin / Q000494:pharmacology; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D000906:Antibodies; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D012433:Ryanodine; D004533:Egtazic Acid; D019284:Thapsigargin; D020866:omega-Conotoxin GVIA; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium