Knockdown of L calcium channel subtypes: differential effects in neuropathic pain.
The maintenance of chronic pain states requires the regulation of gene expression, which relies on an influx of calcium. Calcium influx through neuronal L-type voltage-gated calcium channels (LTCs) plays a pivotal role in excitation-transcription coupling, but the involvement of LTCs in chronic pain remains unclear. We used a peptide nucleic acid (transportan 10-PNA conjugates)-based antisense strategy to investigate the role of the LTC subtypes Ca(V)1.2 and Ca(V)1.3 in long-term pain sensitization in a rat model of neuropathy (spinal nerve ligation). Our results demonstrate that specific knockdown of Ca(V)1.2 in the spinal dorsal horn reversed the neuropathy-associated mechanical hypersensitivity and the hyperexcitability and increased responsiveness of dorsal horn neurons. Intrathecal application of anti-Ca(V)1.2 siRNAs confirmed the preceding results. We also demonstrated an upregulation of Ca(V)1.2 mRNA and protein in neuropathic animals concomitant to specific Ca(V)1.2-dependent phosphorylation of the cAMP response element (CRE)-binding protein (CREB) transcription factor. Moreover, spinal nerve ligation animals showed enhanced transcription of the CREB/CRE-dependent gene COX-2 (cyclooxygenase 2), which also depends strictly on Ca(V)1.2 activation. We propose that L-type calcium channels in the spinal dorsal horn play an important role in pain processing, and that the maintenance of chronic neuropathic pain depends specifically on channels comprising Ca(V)1.2.
Fossat
Pascal
P
INSERM U862, Magendie Neurocenter, Pathophysiology of spinal networks group, 33077 Bordeaux Cedex, France.
Dobremez
Eric
E
Bouali-Benazzouz
Rabia
R
Favereaux
Alexandre
A
Bertrand
Sandrine S
SS
Kilk
Kalle
K
Léger
Claire
C
Cazalets
Jean-René
JR
Langel
Ulo
U
Landry
Marc
M
Nagy
Frédéric
F
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009529:Nicardipine / Q000008:administration & dosage; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012585:Sciatica / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C093712:Cacna1d protein, rat; D009529:Nicardipine; D051546:Cyclooxygenase 2; D050882:CREB-Binding Protein; D002118:Calcium