Document Detail


Inhibition of the PKCγ-ε pathway relieves from meningeal nociception in an animal model: an innovative perspective for migraine therapy?
MedLine Citation:
PMID:  23055050     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There is convincing evidence that nitric oxide (NO) may be a causative factor in the pathogenesis of migraine. We investigated the consequences of NO donors' administration on meningeal processes related to the development of migraine pain in an animal model of meningeal nociception. The administration in mice of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) produced a delayed meningeal upregulation of interleukin-1ß and inducible NO synthase. A thermal allodynia and hyperalgesia devoid of side effects was produced 1 to 4 h after administration. To clarify the cellular pathways modulated by GTN and SNP, we examined the expression of cellular factors involved in pain modulation, such as protein kinase C (PKC) and its downstream effectors. Western blotting experiments showed an upregulation and increased phosphorylation of PKCγ and PKCε within dura mater after NO donors' administration. A dramatic PKC-dependent increase of the phosphorylation of cyclic AMP response element binding protein (CREB) and signal transducer and activator of transcription (STAT)-1 was observed, along with an activation of the nuclear factor-κB (NF-κB) pathway, as reflected by a reduction of the inhibitory protein-κ-Bα (IκBα). Furthermore, the PKC blocker, Calphostin C, prevented the GTN and SNP-induced pain hypersensitivity. These results suggest the relevance of the PKC-mediated pathway in the induction of meningeal nociception and might help clarify the etiopathology of migraines. We can suggest PKC as a new target for migraine pain.
Authors:
Nicoletta Galeotti; Carla Ghelardini
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics     Volume:  10     ISSN:  1878-7479     ISO Abbreviation:  Neurotherapeutics     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-15     Completed Date:  2013-10-24     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  101290381     Medline TA:  Neurotherapeutics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  329-39     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cold Temperature / diagnostic use
Cyclic AMP Response Element-Binding Protein / metabolism
Hot Temperature / diagnostic use
Interleukin-1beta / metabolism
Male
Meninges / physiopathology*
Mice
Migraine Disorders / drug therapy*
Motor Activity / drug effects
NF-kappa B / metabolism
Nitric Oxide Donors / metabolism
Nitric Oxide Synthase Type II / metabolism
Nociception / drug effects*
Pain / drug therapy*
Pain Measurement
Pain Threshold / drug effects
Protein Kinase C / antagonists & inhibitors*
Protein Kinase C-epsilon / antagonists & inhibitors*
Protein Kinase Inhibitors / therapeutic use*
Psychomotor Performance / drug effects
STAT1 Transcription Factor / metabolism
Chemical
Reg. No./Substance:
0/Cyclic AMP Response Element-Binding Protein; 0/Interleukin-1beta; 0/NF-kappa B; 0/Nitric Oxide Donors; 0/Protein Kinase Inhibitors; 0/STAT1 Transcription Factor; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 2.7.1.-/protein kinase C gamma; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-epsilon
Comments/Corrections

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