Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain.
Prostaglandin E(2) (PGE(2)) and epinephrine act directly on nociceptors to produce mechanical hyperalgesia through protein kinase A (PKA) alone or through a combination of PKA, protein kinase C epsilon (PKCepsilon), and extracellular signal-regulated kinase (ERK), respectively. Disruptors of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) markedly attenuated the hyperalgesia in rat paws caused by injection of epinephrine or its downstream mediators. In contrast, the hyperalgesia induced by PGE(2) or its mediators was not affected by any of the cytoskeletal disruptors. These effects were mimicked in vitro, as measured by enhancement of the tetrodotoxin-resistant sodium current. When PGE(2) hyperalgesia was shifted to dependence on PKCepsilon and ERK as well as PKA, as when the tissue is "primed" by prior treatment with carrageenan, it too became dependent on an intact cytoskeleton. Thus, inflammatory mediator-induced mechanical hyperalgesia was differentially dependent on the cytoskeleton such that cytoskeletal dependence correlated with mediation by PKCepsilon and ERK.
Dina
Olayinka A
OA
Department of Medicine, Division of Neuroscience and Biomedical Sciences Program, NIH Pain Center, University of California, San Francisco, San Francisco, CA 94143, USA.
McCarter
Gordon C
GC
de Coupade
Catherine
C
Levine
Jon D
JD
D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases; D003599:Cytoskeleton / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D004594:Electrophysiology; D004837:Epinephrine / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D010146:Pain / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D019707:Receptors, Chemokine; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D015232:Dinoprostone; D004837:Epinephrine