MAPK activation in nociceptive neurons and pain hypersensitivity

Extracellular signal-regulated protein kinase (ERK) is a mitogen-activated protein kinase (MAPK) that mediates intracellular signal transduction in response to a variety of stimuli. ERK is involved in cell proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here, we present recently accumulating data about the roles of MAPK pathways in mediating the neuronal plasticity that contributes to pain hypersensitivity. The phosphorylation of ERK in the dorsal root ganglion (DRG) and dorsal horn neurons occurs in response to noxious stimulation of the peripheral tissue or electrical stimulation to the peripheral nerve, i.e., activity-dependent activation of ERK in nociceptive neurons. In addition, the activation of ERK occurs in these nociceptive neurons after peripheral inflammation and axotomy and contributes to persistent inflammatory and neuropathic pain, via transcriptional regulation of key gene products. On the other hand, peripheral inflammation and axotomy also induces p38 MAPK activation in DRG neurons. Taken together, these findings indicate that activation of MAPK in nociceptive neurons may participate in generating pain hypersensitivity through transcription-dependent and -independent means. Thus, inhibition of MAPK signaling in the primary afferents, as well as in the spinal cord, may provide a fruitful strategy for the development of novel analgesics. (C) 2004 Elsevier Inc. All rights reserved.