Extracellular signal-regulated kinase-1 and -2 are activated by gastric luminal injury in dorsal root ganglion neurons via N-methyl-D-aspartate receptors.
Mitogen activated protein kinases such as phosphorylated extracellular signal-regulated kinase-1 and -2 (pERK 1/2) have been recently demonstrated to play an important role in somatic nociception and hyperalgesia. In the present study we examined whether pERK 1/2 is involved in the response of sensory neurons to a noxious visceral stimulation, in particular, of the gastric mucosa. After induction of gastric injury by oral administration of 0.5M HCl pERK 1/2 expression was determined by Western blotting of caudal thoracic dorsal root ganglia and by immunohistochemistry in stomach-innervating dorsal root ganglion neurons which were retrogradely labeled with True Blue. The content of pERK 1/2 remained unchanged in dorsal root ganglia until 2 h post-HCl, however, was found elevated 4 (approximately 80%) and 6 h (approximately 100%) after HCl administration. True Blue-labeled pERK 1/2-immunoreactive neurons were likewise increased 6 h post-HCl (204%) and were mainly of small size (20-40 microm) and negative for neurofilament 200 (approximately 76%). The majority of these cells also expressed the nociceptive transient receptor potential vanilloid receptor 1 (approximately 70%). The gastric mucosa was simultaneously examined for lesion formation showing highest percentage of damage 6 h post-HCl. Application of a N-methyl-D-aspartate receptor antagonist (MK-801; 100 microg/kg s.c.) significantly reduced HCl-induced pERK 1/2 expression and mucosal lesions 6 h post-HCl. Activation of the extracellular signal-regulated kinase-1 and -2 signaling cascade indicates that visceral primary afferents may sensitize after gastric noxious stimulation involving N-methyl-D-aspartate receptors. The extracellular signal-regulated kinase-1 and -2 pathway therefore may not only be of importance for somatic but also for visceral nociception.
Schicho
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Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria. rudolf.schicho@meduni-graz.at
Liebmann
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Lippe
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D000818:Animals; D004789:Enzyme Activation; D005260:Female; D005727:Ganglia, Spinal / Q000201:enzymology; D005753:Gastric Mucosa / Q000293:injuries; D006851:Hydrochloric Acid / Q000633:toxicity; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013270:Stomach / Q000293:injuries*
D016194:Receptors, N-Methyl-D-Aspartate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006851:Hydrochloric Acid