Inhibition of the PKCγ-ε pathway relieves from meningeal nociception in an animal model: an innovative perspective for migraine therapy?
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.
Department of Preclinical and Clinical Pharmacology, Viale G. Pieraccini 6, Florence, 50139, Italy. nicoletta.galeotti@unifi.it
Nicoletta
N
Galeotti
Carla
C
Ghelardini
D000818:Animals; D015153:Blotting, Western; D003080:Cold Temperature; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006358:Hot Temperature; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008578:Meninges / Q000503:physiopathology*; D051379:Mice; D008881:Migraine Disorders / Q000188:drug therapy*; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D059225:Nociception / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; D052247:Nitric Oxide Synthase Type II; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon