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The Journal of Neuroscience, September 1, 2002, 22(17):7737-7745
Phosphorylation of Extracellular Signal-Regulated Kinase in
Primary Afferent Neurons by Noxious Stimuli and Its Involvement in
Peripheral Sensitization
Yi
Dai1,
Koichi
Iwata2,
Tetsuo
Fukuoka1,
Eiji
Kondo3,
Atsushi
Tokunaga1,
Hiroki
Yamanaka1,
Toshiya
Tachibana1,
Yi
Liu1, and
Koichi
Noguchi1
1 Department of Anatomy and Neuroscience, Hyogo College
of Medicine, Hyogo 663-8501, Japan, 2 Department of
Physiology, Nihon University, School of Dentistry, Tokyo 101-8310, Japan, and 3 Institute for Dental Science, Matsumoto Dental
University, Nagano 399-0781, Japan
Alteration in the intracellular signal transduction pathway in
primary afferent neurons may contribute to pain hypersensitivity. We
demonstrated that very rapid phosphorylation of extracellular signal-regulated protein kinases (pERK) occurred in DRG neurons that
were taking part in the transmission of various noxious signals. The
electrical stimulation of A fibers induced pERK primarily in neurons
with myelinated fibers. c-Fiber activation by capsaicin injection
induced pERK in small neurons with unmyelinated fibers containing
vanilloid receptor-1 (VR-1), suggesting that pERK labeling in DRG
neurons is modality specific. Electrical stimulation at the c-fiber
level with different intensities and frequencies revealed that
phosphorylation of ERK is dependent on the frequency. We examined the
pERK in the DRG after application of natural noxious stimuli and found
a stimulus intensity-dependent increase in labeled cell size and in the
number of activated neurons in the c- and A-fiber population.
Immunohistochemical double labeling with phosphorylated ERK/VR-1 and
pharmacological study demonstrated that noxious heat stimulation
induced pERK in primary afferents in a VR-1-dependent manner. Capsaicin
injection into the skin also increased pERK labeling significantly in
peripheral fibers and terminals in the skin, which was prevented by a
mitogen-activated protein kinase/ERK kinase inhibitor,
1,4-diamino-2,3-dicyano-1,4-bis(2-aminopheylthio)butadiene (U0126). Behavioral experiments showed that U0126
dose-dependently attenuated thermal hyperalgesia after capsaicin
injection and suggested that the activation of ERK pathways in primary
afferent neurons is involved in the sensitization of primary afferent
neurons. Thus, pERK in primary afferents by noxious stimulation
in vivo showed distinct characteristics of expression
and may be correlated with the functional activity of primary afferent neurons.
Key words:
extracellular signal-regulated kinase; phosphorylation; dorsal root ganglion; pain stimuli; MAP kinase; peripheral
sensitization
Copyright © 2002 Society for Neuroscience 0270-6474/02/22177737-09$05.00/0
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