Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia.
Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of p38 mitogen-activated protein kinase occurred in dorsal root ganglion (DRG) neurons that were participating in the transmission of noxious signals. Capsaicin injection induced phosphorylated-p38 (p-p38) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-p38 labeling in the DRG after noxious thermal stimuli and found a stimulus intensity-dependent increase in labeled cell size and the number of activated neurons. Most of these p-p38-immunoreactive (IR) neurons were small- and medium-sized neurons, which coexpressed transient receptor potential ion channel TRPV1 and phosphorylated-extracellular signal-regulated protein kinase. Intrathecal administration of the p38 inhibitor, FR167653, reversed the thermal hyperalgesia produced by the capsaicin injection. Inhibition of p38 activation was confirmed by the decrease in the number of p-p38-IR neurons in the DRG following capsaicin injection. Taken together, these findings suggest that the activation of p38 pathways in primary afferents by noxious stimulation in vivo may be, at least in part, correlated with functional activity, and further, involved in the development of thermal hyperalgesia.
Mizushima
Toshiyuki
T
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Obata
Koichi
K
Yamanaka
Hiroki
H
Dai
Yi
Y
Fukuoka
Tetsuo
T
Tokunaga
Atsushi
A
Mashimo
Takashi
T
Noguchi
Koichi
K
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004789:Enzyme Activation / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects / Q000528:radiation effects; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C104334:FR 167653; D007473:Ion Channels; D016900:Neurofilament Proteins; D011720:Pyrazoles; D011725:Pyridines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C051774:neurofilament protein H; D048053:Mitogen-Activated Protein Kinase 6; D048051:p38 Mitogen-Activated Protein Kinases; D002211:Capsaicin