Pathological pain, normally referring to tissue injury-induced inflammatory pain and nerve injury-induced neuropathic pain, is an expression of neural plasticity. Injuries and intense noxious stimuli result in pain hypersensitivity, which is contributed by peripheral sensitization (increased sensitivity of primary sensory nociceptors) and central sensitization (increased sensitivity of spinal dorsal hom and other CNS neurons). Activation of several protein kinases causes both forms of sensitization via posttranslational regulation, such as phosphorylation of key membrane receptors and channels. In particular, activation of multiple signal cascades converge on the activation of MAPK (mitogen-activated protein kinase). Activation of MAPK family members of ERK and p38 by nociceptive activity, growth factors, and inflammatory mediators in primary sensory and secondary order neurons, not only results in posttranslational modification, but also increases the expression of numerous genes via transcriptional and non-transcriptional regulation. Eventually this activation contributes to the development and maintenance of heightened pain sensitivity following injury.