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 c urrent methods of analgesia are often only partially successful. Although p rotein kinase C (PKC) enhances nociceptor function, it is not known which P KC isozymes contribute. Here, we show that epinephrine-induced mechanical a nd thermal hyperalgesia and acetic acid-associated hyperalgesia are markedl y attenuated in PKC epsilon mutant mice, but baseline nociceptive threshold s are normal. Moreover, epinephrine-, carrageenan-, and nerve growth factor - (NGF-) induced hyperalgesia in normal rats, and epinephrine-induced enhan cement of tetrodotoxin-resistant Na+ current (TTX-R I-Na) in cultured rat d orsal root ganglion (DRG) neurons, are inhibited by a PKC epsilon-selectiiv e inhibitor peptide. Our findings indicate that PKC epsilon regulates nocic eptor function and suggest that PKC epsilon inhibitors could prove useful i n the treatment of pain.