Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction
and play critical roles in regulating neural plasticity and inflammatory responses.
The MAPK family consists of three major members: extracellular signal-regulated kinases
(ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling
pathways. Accumulating evidence shows that all three MAPK pathways contribute to pain
sensitization after tissue and nerve injury via distinct molecular and cellular mechanisms.
Activation (phosphorylation) of MAPKs under different persistent pain conditions results
in the induction and maintenance of pain hypersensitivity via non-transcriptional
and transcriptional regulation. In particular, ERK activation in spinal cord dorsal
horn neurons by nociceptive activity, via multiple neurotransmitter receptors, and
using different second messenger pathways plays a critical role in central sensitization
by regulating the activity of glutamate receptors and potassium channels and inducing
gene transcription. ERK activation in amygdala neurons is also required for inflammatory
pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated
in spinal glial cells (microglia vs astrocytes), leading to the synthesis of proinflammatory/pronociceptive
mediators, thereby enhancing and prolonging pain. Inhibition of all three MAPK pathways
has been shown to attenuate inflammatory and neuropathic pain in different animal
models. Development of specific inhibitors for MAPK pathways to target neurons and
glial cells may lead to new therapies for pain management. Although it is well documented
that MAPK pathways can increase pain sensitivity via peripheral mechanisms, this review
will focus on central mechanisms of MAPKs, especially ERK.