Journal
JOURNAL OF NEUROSCIENCE
Volume 21, Issue 17, Pages 6933-6939Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.21-17-06933.2001
Keywords
extracellular signal-regulated kinase; mitogen-activated protein kinase; protein kinase C epsilon; protein kinase A; epinephrine; pain; hyperalgesia; nociceptor; Ras; beta-adrenergic receptor; mitogen and extracellular signal-regulated kinase kinase; G-protein
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Funding
- NIAAA NIH HHS [AA10036] Funding Source: Medline
- NINDS NIH HHS [NS21647] Funding Source: Medline
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Inflammatory pain, characterized by a decrease in mechanical nociceptive threshold (hyperalgesia), arises through actions of inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKC epsilon), have been implicated in primary afferent nociceptor sensitization. Here we describe a third, independent pathway that involves activation of extracellular signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalgesia by direct action at beta (2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal root ganglion cells. This was inhibited by a beta (2)-adrenergic receptor blocker and by an inhibitor of mitogen and extracellular signal-regulated kinase kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G(i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-induced hyperalgesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produced hyperalgesia that was unaffected by PKA or PKC epsilon inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKC epsilon was unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts 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 new class of analgesic agents.
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