MAP kinase and pain

Ru Rong Ji, Robert W. Gereau IV, Marzia Malcangio, Gary R. Strichartz

Research output: Contribution to journalReview article

669 Scopus citations


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.

Original languageEnglish
Pages (from-to)135-148
Number of pages14
JournalBrain Research Reviews
Issue number1
StatePublished - Apr 1 2009


  • Amygdala
  • Astrocyte
  • Central sensitization
  • Inflammatory pain
  • MAPK
  • Microglia
  • Neural plasticity
  • Neuropathic pain
  • Spinal cord

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    Ji, R. R., Gereau IV, R. W., Malcangio, M., & Strichartz, G. R. (2009). MAP kinase and pain. Brain Research Reviews, 60(1), 135-148.