A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice.
There is great interest in discovering new targets for pain therapy since current methods of analgesia are often only partially successful. Although protein kinase C (PKC) enhances nociceptor function, it is not known which PKC isozymes contribute. Here, we show that epinephrine-induced mechanical and thermal hyperalgesia and acetic acid-associated hyperalgesia are markedly attenuated in PKCepsilon mutant mice, but baseline nociceptive thresholds are normal. Moreover, epinephrine-, carrageenan-, and nerve growth factor- (NGF-) induced hyperalgesia in normal rats, and epinephrine-induced enhancement of tetrodotoxin-resistant Na+ current (TTX-R I(Na)) in cultured rat dorsal root ganglion (DRG) neurons, are inhibited by a PKCepsilon-selective inhibitor peptide. Our findings indicate that PKCepsilon regulates nociceptor function and suggest that PKCepsilon inhibitors could prove useful in the treatment of pain.
Khasar
S G
SG
Department of Internal Medicine and Oral Surgery, National Institutes of Health/University of California, USA.
Lin
Y H
YH
Martin
A
A
Dadgar
J
J
McMahon
T
T
Wang
D
D
Hundle
B
B
Aley
K O
KO
Isenberg
W
W
McCarter
G
G
Green
P G
PG
Hodge
C W
CW
Levine
J D
JD
Messing
R O
RO
D019342:Acetic Acid; D000698:Analgesia; D000700:Analgesics; D000818:Animals; D002351:Carrageenan; D004791:Enzyme Inhibitors; D004837:Epinephrine; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D020932:Nerve Growth Factor; D009619:Nociceptors / Q000502:physiology*; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
D000700:Analgesics; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D015222:Sodium Channels; D013779:Tetrodotoxin; D002351:Carrageenan; D020932:Nerve Growth Factor; D011493:Protein Kinase C; D019342:Acetic Acid; D004837:Epinephrine