MAP kinases (MAPKs) are crucial for intracellular signaling and regulate neural plasticity and inflammatory responses. The MAPK family includes three main members: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), each involved in distinct mechanisms of pain sensitization following tissue and nerve injury. Activation of these pathways, through phosphorylation, contributes to the induction and maintenance of pain hypersensitivity via both non-transcriptional and transcriptional regulation. ERK activation in spinal cord dorsal horn neurons, via multiple neurotransmitter receptors and second messenger pathways, plays a critical role in central sensitization by regulating glutamate receptors and potassium channels, as well as 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. ERK1/2 are activated by upstream kinase MEK1 and MEK2 and play a critical role in central sensitization. ERK activation in SCDH neurons is dependent on nociceptive activity and is involved in the induction and maintenance of neural plasticity, such as peripheral and central sensitization. ERK activation is also involved in the regulation of various postsynaptic receptors and the production of pronociceptive mediators. ERK activation in spinal glial cells is necessary for the development and maintenance of neuropathic pain. ERK activation integrates multiple signaling pathways in SCDH neurons, contributing to central sensitization and inflammatory pain. ERK activation in SCDH neurons contributes to central sensitization and inflammatory pain by promoting intracellular events that contribute to central sensitization. ERK activation in amygdala neurons and spinal glial cells also contributes to inflammatory pain. ERK activation in spinal glial cells and neuropathic pain is essential for intracellular signaling leading to the production of proinflammatory and pronociceptive mediators. p38 and JNK also play important roles in pain regulation, with p38 being activated by cellular stress and proinflammatory cytokines, and JNK being involved in neurodegeneration and apoptosis. Inhibitors of ERK, p38, and JNK have been shown to effectively alleviate inflammatory and neuropathic pain in different animal models. These inhibitors may be useful for testing the efficacy andMAP kinases (MAPKs) are crucial for intracellular signaling and regulate neural plasticity and inflammatory responses. The MAPK family includes three main members: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), each involved in distinct mechanisms of pain sensitization following tissue and nerve injury. Activation of these pathways, through phosphorylation, contributes to the induction and maintenance of pain hypersensitivity via both non-transcriptional and transcriptional regulation. ERK activation in spinal cord dorsal horn neurons, via multiple neurotransmitter receptors and second messenger pathways, plays a critical role in central sensitization by regulating glutamate receptors and potassium channels, as well as 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. ERK1/2 are activated by upstream kinase MEK1 and MEK2 and play a critical role in central sensitization. ERK activation in SCDH neurons is dependent on nociceptive activity and is involved in the induction and maintenance of neural plasticity, such as peripheral and central sensitization. ERK activation is also involved in the regulation of various postsynaptic receptors and the production of pronociceptive mediators. ERK activation in spinal glial cells is necessary for the development and maintenance of neuropathic pain. ERK activation integrates multiple signaling pathways in SCDH neurons, contributing to central sensitization and inflammatory pain. ERK activation in SCDH neurons contributes to central sensitization and inflammatory pain by promoting intracellular events that contribute to central sensitization. ERK activation in amygdala neurons and spinal glial cells also contributes to inflammatory pain. ERK activation in spinal glial cells and neuropathic pain is essential for intracellular signaling leading to the production of proinflammatory and pronociceptive mediators. p38 and JNK also play important roles in pain regulation, with p38 being activated by cellular stress and proinflammatory cytokines, and JNK being involved in neurodegeneration and apoptosis. Inhibitors of ERK, p38, and JNK have been shown to effectively alleviate inflammatory and neuropathic pain in different animal models. These inhibitors may be useful for testing the efficacy and