Knockdown of L Calcium Channel Subtypes: Differential Effects in Neuropathic Pain

被引:94
作者
Fossat, Pascal [1 ,2 ]
Dobremez, Eric [1 ,2 ]
Bouali-Benazzouz, Rabia [1 ,2 ]
Favereaux, Alexandre [1 ,2 ]
Bertrand, Sandrine S. [2 ,3 ]
Kilk, Kalle [4 ,5 ]
Leger, Claire [1 ,2 ]
Cazalets, Jean-Rene [2 ,3 ]
Langel, Uelo [4 ]
Landry, Marc [1 ,2 ]
Nagy, Frederic [1 ,2 ]
机构
[1] INSERM, U862, Magendie Neuroctr, Pathophysiol Spinal Networks Grp, F-33077 Bordeaux, France
[2] Bordeaux Univ, F-33076 Bordeaux, France
[3] CNRS, UMR 5227, Lab Mouvement Adaptat Cognit, F-33076 Bordeaux, France
[4] Stockholm Univ, Dept Neurochem, S-10691 Stockholm, Sweden
[5] Univ Tartu, Fac Med, Inst Biochem, EE-50411 Tartu, Estonia
关键词
ELEMENT-BINDING PROTEIN; DORSAL-HORN NEURONS; SPINAL NERVE LIGATION; MECHANICAL ALLODYNIA; CREB PHOSPHORYLATION; NUCLEAR CALCIUM; GENE-EXPRESSION; CA2+ CHANNELS; KINASE-C; CORD;
D O I
10.1523/JNEUROSCI.3145-09.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1073 / 1085
页数:13
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