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Donnerer, J; Liebmann, I.
The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons.
Pharmacology. 2006; 77(3):144-149 Doi: 10.1159/000094022
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Leading authors Med Uni Graz: Donnerer Josef
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Abstract:: Primary sensory neurons respond to a vigorous excitation via the capsaicin receptor/TRPV1 cation channel by a phosphorylation of the Jak/STAT pathway as measured by phospho-STAT3, and of the Ras/Raf-MAPK pathway as measured by phospho-MAPK/ERK1/2. In the present investigation a possible involvement of NK1 receptors in the capsaicin-induced activation of these signal transduction pathways was investigated by protein extraction and Western immunoblotting. Phospho-MAPK/ERK1/2 and phospho-STAT3 were determined in the dorsal root ganglia (DRG) and in the sciatic nerve of rats at 3 and 6 h following a systemic capsaicin treatment without or with the pretreatment of the selective NK1 receptor antagonist SR140333 (1 mg/kg s.c.; 3 h before capsaicin). Capsaicin evoked a threefold increase in phospho-ERK in the sciatic nerve and a two- to threefold increase in the DRG at 3 h and 6 h after the treatment. SR140333 markedly attenuated the capsaicin-induced increase in phosphorylated ERK. In the sciatic nerve the difference was significant at each individual time point (3 and 6 h, p < 0.001). In the DRG the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), but not when individual time points were considered. Capsaicin evoked a four- to fivefold increase in phospho-STAT3 in the sciatic nerve and a twofold increase in the DRG at 3 and 6 h after the treatment. SR140333 less markedly attenuated the capsaicin-induced increase in phosphorylated STAT3: whereas in the sciatic nerve the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), no such treatment effect of SR140333 was observed in the DRG. The expression of TRPV1 mRNA, a specific marker of capsaicin-sensitive small sensory neurons, was investigated by RT-PCR 4 days after the capsaicin treatment. Treatment of rats with SR140333 had no influence on the long-term downregulation of TRPV1 mRNA by capsaicin. Based on the present results and previous findings it can be postulated that the capsaicin-induced ERK phosphorylation in sensory neurons is not a direct effect by capsaicin, but that rather substance P release from the stimulated sensory neurons with an NK1-mediated nerve growth factor (NGF) production is involved.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Capsaicin - toxicity; Extracellular Signal-Regulated MAP Kinases - metabolism; Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism; Gene Expression Regulation - drug effects; Male -; Neurokinin-1 Receptor Antagonists -; Neurons, Afferent - drug effects Neurons, Afferent - metabolism; Phosphorylation - drug effects; Piperidines - pharmacology; Quinuclidines - pharmacology; RNA, Messenger - metabolism; Rats -; Rats, Sprague-Dawley -; STAT3 Transcription Factor - metabolism; Sciatic Nerve - drug effects Sciatic Nerve - metabolism; TRPV Cation Channels - genetics TRPV Cation Channels - metabolism
Find related publications in this database (Keywords): intracellular signaling; ERK and STAT3 phosphorylation; vanilloid receptor; TRPV1 mRNA; NK1 receptor antagonist SR140333