Central sensitization is a phenomenon where nociceptor inputs trigger prolonged but reversible increases in the excitability and synaptic efficacy of neurons in central nociceptive pathways, leading to pain hypersensitivity. It manifests as dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. Central sensitization can be elicited in human volunteers by various noxious stimuli and results in secondary changes in brain activity detectable by electrophysiological or imaging techniques. Studies in clinical cohorts show changes in pain sensitivity that suggest central sensitization contributes to pain phenotypes in conditions like fibromyalgia, osteoarthritis, headache, and neuropathic pain. The comorbidity of these pain hypersensitivity syndromes, their similar clinical presentation, and response to centrally acting analgesics may reflect a commonality of central sensitization in their pathophysiology. The question of whether individuals have a higher inherited propensity for central sensitization remains unresolved. Diagnostic criteria for central sensitization would aid in phenotyping patients for treatments that normalize hyperexcitable central neural activity. Central sensitization is a robust phenomenon, readily induced in human volunteers by diverse nociceptor activation methods. It can be elicited by skin, muscle, or visceral organs and typically presents as dynamic tactile allodynia and punctate hyperalgesia, with possible enhanced pressure or thermal sensitivity. While there is a homosynaptic aspect, its major manifestation is heterosynaptic, and it is not equivalent to long-term potentiation (LTP) in the cortex. Central sensitization is sensitive to pharmacological interventions and is a useful tool for assessing drug activity on centrally driven pain hypersensitivity. Data from human volunteer studies show that central sensitization contributes to clinical pain syndromes, including rheumatoid arthritis, osteoarthritis, temporomandibular disorders, fibromyalgia, and neuropathic pain. Central sensitization is a significant contributor to the pain phenotype in these conditions and is a target for treatment. The role of central sensitization in chronic pain conditions like fibromyalgia and headache is well established, with evidence of widespread central sensitization and the effectiveness of centrally acting drugs in reducing pain. Central sensitization is a key factor in the pathophysiology of various pain conditions and is a target for treatment strategies.Central sensitization is a phenomenon where nociceptor inputs trigger prolonged but reversible increases in the excitability and synaptic efficacy of neurons in central nociceptive pathways, leading to pain hypersensitivity. It manifests as dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. Central sensitization can be elicited in human volunteers by various noxious stimuli and results in secondary changes in brain activity detectable by electrophysiological or imaging techniques. Studies in clinical cohorts show changes in pain sensitivity that suggest central sensitization contributes to pain phenotypes in conditions like fibromyalgia, osteoarthritis, headache, and neuropathic pain. The comorbidity of these pain hypersensitivity syndromes, their similar clinical presentation, and response to centrally acting analgesics may reflect a commonality of central sensitization in their pathophysiology. The question of whether individuals have a higher inherited propensity for central sensitization remains unresolved. Diagnostic criteria for central sensitization would aid in phenotyping patients for treatments that normalize hyperexcitable central neural activity. Central sensitization is a robust phenomenon, readily induced in human volunteers by diverse nociceptor activation methods. It can be elicited by skin, muscle, or visceral organs and typically presents as dynamic tactile allodynia and punctate hyperalgesia, with possible enhanced pressure or thermal sensitivity. While there is a homosynaptic aspect, its major manifestation is heterosynaptic, and it is not equivalent to long-term potentiation (LTP) in the cortex. Central sensitization is sensitive to pharmacological interventions and is a useful tool for assessing drug activity on centrally driven pain hypersensitivity. Data from human volunteer studies show that central sensitization contributes to clinical pain syndromes, including rheumatoid arthritis, osteoarthritis, temporomandibular disorders, fibromyalgia, and neuropathic pain. Central sensitization is a significant contributor to the pain phenotype in these conditions and is a target for treatment. The role of central sensitization in chronic pain conditions like fibromyalgia and headache is well established, with evidence of widespread central sensitization and the effectiveness of centrally acting drugs in reducing pain. Central sensitization is a key factor in the pathophysiology of various pain conditions and is a target for treatment strategies.