Mitogen-activated protein kinases (MAPKs) play crucial roles in regulating neural plasticity and inflammatory responses, with three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK). These MAPKs are activated under different persistent pain conditions, leading to the induction and maintenance of pain hypersensitivity through both non-transcriptional and transcriptional mechanisms. ERK activation in spinal cord dorsal horn neurons is critical for central sensitization, regulating glutamate receptors and potassium channels and inducing gene transcription. In the amygdala, ERK activation contributes to inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells, leading to the synthesis of proinflammatory/pronociceptive mediators, enhancing and prolonging pain. Inhibition of these MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in various animal models. Development of specific inhibitors for MAPK pathways may lead to new therapies for pain management. This review focuses on the central mechanisms of MAPKs, particularly ERK, in pain regulation.Mitogen-activated protein kinases (MAPKs) play crucial roles in regulating neural plasticity and inflammatory responses, with three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK). These MAPKs are activated under different persistent pain conditions, leading to the induction and maintenance of pain hypersensitivity through both non-transcriptional and transcriptional mechanisms. ERK activation in spinal cord dorsal horn neurons is critical for central sensitization, regulating glutamate receptors and potassium channels and inducing gene transcription. In the amygdala, ERK activation contributes to inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells, leading to the synthesis of proinflammatory/pronociceptive mediators, enhancing and prolonging pain. Inhibition of these MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in various animal models. Development of specific inhibitors for MAPK pathways may lead to new therapies for pain management. This review focuses on the central mechanisms of MAPKs, particularly ERK, in pain regulation.