The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons.
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.
Donnerer
J
J
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, Austria. josef.donnerer@meduni-graz.at
Liebmann
I
I
D000818:Animals; D002211:Capsaicin / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C085215:SR 140333; D048049:Extracellular Signal-Regulated MAP Kinases; D002211:Capsaicin