Nociceptor sensitization by extracellular signal-regulated kinases

Inflammatory pain, characterized by a decrease in mechanical nociceptive th reshold (hyperalgesia), arises through actions of inflammatory mediators, m any of which sensitize primary afferent nociceptors via G-protein-coupled r eceptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKC epsilon), have b een implicated in primary afferent nociceptor sensitization. Here we descri be a third, independent pathway that involves activation of extracellular s ignal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalg esia by direct action at beta (2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal ro ot ganglion cells. This was inhibited by a beta (2)-adrenergic receptor blo cker and by an inhibitor of mitogen and extracellular signal-regulated kina se kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G (i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-ind uced hyperalgesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produ ced hyperalgesia that was unaffected by PKA or PKC epsilon inhibitors. Conv ersely, hyperalgesia produced by agents that activate PKA or PKC epsilon wa s unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade a cts independent of PKA or PKC epsilon as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for a ne w class of analgesic agents.