Pain sensing neurons in the periphery (called nociceptors) and the central neurons that receive their projections show remarkable plasticity following injury. differences will be highlighted and their role in causing chronic pain will be discussed. Arising from these data is the striking argument that chronic pain is a disease of the nervous system which distinguishes this phenomena from acute pain that is frequently a symptom alerting the organism to injury. This argument has important implications for the development of disease modifying therapeutics. Introduction: pain plasticity and “pain memory” A core feature of all nervous systems is an ability to adapt to sensory information. This adaptive process is referred to as plasticity and the study of neuronal plasticity has led to some of the most exciting advances in modern biological research. The pain system comprised of peripheral neurons responsible for detecting damaging or potentially damaging peripheral stimuli called nociceptors and the neurons of the CNS that receive direct or indirect inputs from these neurons rapidly change upon injury. In almost all studied cases this adaptation results in an amplification of signaling (Woolf and Walters 1991 This pain amplification is thought to underlie some important psychophysical aspects of pain such as an enhanced response to a normally noxious stimulus (hyperalgesia) and a noxious response to a normally innocuous stimulus (allodynia (Cervero 1996 Plasticity may also lead to changes in nociceptors or other neurons in the pain pathway that cause them to fire action potentials without any direct stimulation (ectopic activity) or fire continuously following stimulation (afterdischarge) both of which likely contribute to what is commonly called spontaneous pain that is a common feature of chronic neuropathic pain (Lisney and Devor 1987 Devor et al. 1994 While all of these states can exist acutely following an injury they are also prominent features of chronic pain disorders. Delsoline On the most general level plasticity in the pain system occurs at two locations the primary afferent nociceptor (Reichling et al. 2013 and at synapses receiving nociceptive input throughout the CNS (Ji et al. 2003 Woolf 2007 Latremoliere and Woolf 2009 Preclinical models of acute and chronic inflammatory pain as well as models of neuropathic pain have revealed a plethora of molecular targets that have advanced our understanding of how chronic pain develops as well as revealing important potential therapeutic intervention points. EMR1 These experimental studies have also revealed a striking similarity in Delsoline mechanisms underlying pain amplification and learning and memory in areas of the brain such as hippocampus and cerebral cortex (Ji et al. 2003 Sandkuhler 2007 Ruscheweyh et al. 2011 These findings have given rise to the Delsoline idea that a “pain memory” is encoded within the nervous system and that reversing this pain memory may be the key to terminating chronic pain disorders (Reichling and Delsoline Levine 2009 Price and Ghosh 2013 Reichling et al. 2013 In other words reversing plasticity Delsoline in pain circuits may provide the opportunity to permanently alleviate chronic pain. While the term “pain memory” has been used in a variety of forms for decades the first specific uses in the scientific literature to our knowledge can be attributed to Ronald Melzack one of the experimental pioneers widely credited with advancing pain science into the modern age of neuroscience. In 1979 Dennis and Melzack described a series of experiments where painful irritation of the rat paw prior to a denervation injury led to an exacerbation of neuropathic pain (Dennis and Melzack 1979 They hypothesized that this pre-irritation led to the generation of a “pain memory” that could not be repressed by descending pain modulation centers due to the subsequent nerve injury and therefore persisted unabated after the nerve injury. Subsequently in 1990 Katz and Melzack presented this same term in the context of phantom limb pain (Katz and Melzack 1990 pain arising in a limb that has been amputated. They postulated that this sort of pain occurs due to the “memory” of pain that was caused by damage to the limb that was subsequently amputated. Since many amputations occur due to injury to a limb that is irreparable this could explain this common clinical finding in amputees. While.