Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain.
Increased production of calcitonin gene-related peptide (CGRP) in sensory neurons is implicated in inflammatory pain. The inflammatory site is acidic due to proton release from infiltrating inflammatory cells. Acid activation of peripheral nociceptors relays pain signals to the CNS. Here, we examined whether acid activated the transient receptor potential vanilloid subtype 1 (Trpv1), a widely recognized acid-sensing nociceptor and subsequently increased CGRP expression. Chemically induced inflammation was associated with thermal hyperalgesia and increased CGRP expression in dorsal root ganglion (DRG) in rats. In organ cultures of DRG, acid (pH 5.5) elevated CGRP expression and the selective Trpv1 antagonist 5'-Iodoresiniferatoxin decreased it. Trpv1-deficient DRG showed reduced CGRP increase by acid. Of note, many of CGRP/Trpv1-positive DRG neurons exhibited the phosphorylation of cAMP response element-binding protein (CREB), a nociceptive transcription factor. Knockdown of CREB by small interfering RNA or a dominant-negative form of CREB diminished acid-elevated CGRP expression. Acid elevated the transcriptional activity of CREB, which in turn stimulated CGRP gene promoter activity. These effects were inhibited by a Ca(2+)/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. In conclusion, our results suggest that inflammatory acidic environments activate Trpv1, leading to an up-regulation of CGRP expression via CaMK-CREB cascade, a series of events that may be associated with inflammatory pain.
Department of Molecular and Cellular Biology, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan.
Masako
M
Nakanishi
Kenji
K
Hata
Tomotaka
T
Nagayama
Teruhisa
T
Sakurai
Toshihiko
T
Nishisho
Hiroki
H
Wakabayashi
Toru
T
Hiraga
Shigeyuki
S
Ebisu
Toshiyuki
T
Yoneda
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015640:Ion Channel Gating; D051379:Mice; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010146:Pain / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011522:Protons; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
D017362:Cyclic AMP Response Element-Binding Protein; D011522:Protons; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide