title: Knockdown of L calcium channel subtypes: differential effects in neuropathic pain.
abstract: 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.
authors.affiliation: INSERM U862, Magendie Neurocenter, Pathophysiology of spinal networks group, 33077 Bordeaux Cedex, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fossat
authors.forename: Eric
authors.initials: E
authors.lastname: Dobremez
authors.forename: Rabia
authors.initials: R
authors.lastname: Bouali-Benazzouz
authors.forename: Alexandre
authors.initials: A
authors.lastname: Favereaux
authors.forename: Sandrine S
authors.initials: SS
authors.lastname: Bertrand
authors.forename: Kalle
authors.initials: K
authors.lastname: Kilk
authors.forename: Claire
authors.initials: C
authors.lastname: Léger
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Cazalets
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
authors.forename: Marc
authors.initials: M
authors.lastname: Landry
authors.forename: Frédéric
authors.initials: F
authors.lastname: Nagy
mesh_terms: 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
chemical_list: 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