A novel nociceptor signaling pathway revealed in protein kinase C ε 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 PKC epsilon 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 PKC epsilon-selectiive inhibitor peptide. Our findings indicate that PKC epsilon regulates nociceptor function and suggest that PKC epsilon inhibitors could prove useful in the treatment of pain.