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 0.5 M HCI 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-HCI, however, was found elevated 4 (similar to 80%) and 6 h (similar to 100%) after HCI administration. True Blue-labeled pERK 1/2-immunoreactive neurons were likewise increased 6 h post-HCI (204%) and were mainly of small size (20-40 mu m) and negative for neurofilament 200 (similar to 76%). The majority of these cells also expressed the nociceptive transient receptor potential vanilloid receptor 1 (similar to 70%). The gastric mucosa was simultaneously examined for lesion formation showing highest percentage of damage 6 h post-HCI. Application of a N-methyl-D-aspartate receptor antagonist (MK-801; 100 mu g/kg s.c.) significantly reduced HCI-induced pERK 1/2 expression and mucosal lesions 6 h post-HCI. 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. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.