Extracellular signaling-regulated kinase-1 and -2 (ERK 1/2) mediate referred hyperalgesia in a murine model of visceral pain.
We have investigated the role of spinal extracellular signaling-regulated kinase-1 and -2 (ERK1/2) in a model of visceral pain and hyperalgesia induced by intracolonic instillation of irritants in adult mice. Instillation of either capsaicin or mustard oil induced a significant activation of lumbosacral spinal ERK1/2, measured by immunoblot, with a peak 2.4-fold increase over control levels between 45 and 90 min post-treatment. Intracolonic saline did not produce significant activation of lumbosacral spinal ERK1/2, and none of the treatments evoked ERK1/2 activation in thoracic or cervical spinal cord. These studies suggested a preferential nuclear localization, which was explored by subcellular fractionation. Both mustard oil and capsaicin produced a redistribution of phosphorylated ERK1/2 from cytosol into the nucleus that was statistically significant at 45 min after treatment. Spinal ERK1/2 activation with capsaicin treatment correlated with the development of prolonged referred hyperalgesia. The upstream inhibitor of ERK phosphorylation, U0126 (100-400 microg/kg, i.v., 10 min pre-capsaicin), dose-dependently inhibited referred hyperalgesia 3-6 h after capsaicin. Treatment with U0126 did not affect spontaneous pain behavior or colon inflammation. Our data show that ERK activation plays a specific role in maintaining prolonged referred (secondary) hyperalgesia in visceral pain. The time course and subcellular localization of the effects observed suggest that ERK is involved in transcriptional events underlying the maintenance of secondary hyperalgesia.
Galan
Alba
A
Department of Physiology, University of Alcalá, Alcalá de Henares, E-28871 Madrid, Spain.
Cervero
Fernando
F
Laird
Jennifer M A
JM
D000470:Alkaloids / Q000008:administration & dosage; D000818:Animals; D001522:Behavior, Animal; D002070:Butadienes / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009149:Mustard Plant; D009570:Nitriles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D010936:Plant Extracts / Q000008:administration & dosage; D010938:Plant Oils; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D017833:Visceral Afferents / Q000503:physiopathology*
D000470:Alkaloids; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D010936:Plant Extracts; D010938:Plant Oils; C113580:U 0126; C030167:capaurine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C027793:mustard oil