Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C

We have identified a mechanism, mediated by the epsilon isozyme of protein kinase C (PKC epsilon) in peripheral neurons, which may have a role in chro nic inflammatory pain. Acute inflammation, produced by carrageenan injectio n in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after carrageenan, injection of the inflamma tory mediators prostaglandin E-2 or 5-hydroxytryptamine or of an adenosine A(2) agonist into the same site induced a markedly prolonged hyperalgesia ( >24 hr compared with 5 hr or less in control rats not pretreated with carra geenan). A nonselective inhibitor of several PKC isozymes and a selective P KCe inhibitor antagonized this prolonged hyperalgesic response equally. Acu te carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. H owever, these antagonists did not inhibit development of the hypersensitivi ty to inflammatory mediators. Our findings indicate that different second m essenger pathways underlie acute and prolonged inflammatory pain.