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The Journal of Neuroscience, September 1, 2001, 21(17):6933-6939
Nociceptor Sensitization by Extracellular Signal-Regulated
Kinases
K. O.
Aley1,
Annick
Martin2,
Thomas
McMahon2,
Janine
Mok1,
Jon D.
Levine1, and
Robert O.
Messing2
1 Departments of Medicine and Oral Surgery, National
Institutes of Health Pain Center at the University of California, San
Francisco, San Francisco, California 94143, and the
2 Department of Neurology, Ernest Gallo Clinic and Research
Center at the University of California, San Francisco, Emeryville,
California 94608
Inflammatory pain, characterized by a decrease in mechanical
nociceptive threshold (hyperalgesia), arises through actions of
inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKC ), have been implicated in primary afferent nociceptor sensitization. Here we describe a third,
independent pathway that involves activation of extracellular
signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces
hyperalgesia by direct action at  2-adrenergic receptors
on primary afferent nociceptors, stimulated phosphorylation of ERK1/2
in cultured rat dorsal root ganglion cells. This was inhibited by a
2-adrenergic receptor blocker and by an inhibitor of
mitogen and extracellular signal-regulated kinase kinase (MEK), which
phosphorylates and activates ERK1/2. Inhibitors of
Gi/o-proteins, Ras farnesyltransferases, and MEK decreased
epinephrine-induced hyper-algesia. In a similar manner,
phosphorylation of ERK1/2 was also decreased by these inhibitors. Local
injection of dominant active MEK produced hyperalgesia that was
unaffected by PKA or PKC inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKC was unaffected by MEK
inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts independent of PKA or PKC as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for
a new class of analgesic agents.
Key words:
extracellular signal-regulated kinase; mitogen-activated
protein kinase; protein kinase C; protein kinase A; epinephrine; pain; hyperalgesia; nociceptor; Ras; -adrenergic receptor; mitogen
and extracellular signal-regulated kinase kinase; G-protein
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176933-07$05.00/0
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