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Central sensitization
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== History == === Secondary hyperalgesia === In 1950, Hardy and colleagues proposed that there were two types of [[hyperalgesia]].<ref>{{Cite journal | last = Hardy | first = James D. | last2 = Wolff | first2 = Harold G. | last3 = Goodell | first3 = Helen | date = 1950-01-01 | title = Experimental Evidence on The Nature of Cutaneous Hyperalgesia | url = http://dx.doi.org/10.1172/jci102227 | journal = Journal of Clinical Investigation | volume = 29 | issue = 1 | pages = 115–140|doi=10.1172/jci102227|issn=0021-9738}}</ref> Primary hyperalgesia refers to pain sensitivity at the site of an injury, while secondary hyperalgesia refers to enhanced sensation in surrounding undamaged tissues, sometimes in remote sites distant from the injury. Hardy and colleagues speculated the former to be mediated by peripheral mechanisms, while the latter was suspected to be the result of "a central excitatory state", involving lasting changes in the responsiveness of the central nervous system.<ref name=":8">{{Cite journal | last = Coderre | first = Terence J. | last2 = Katz | first2 = Joel | last3 = Vaccarino | first3 = Anthony L. | last4 = Melzack | first4 = Ronald | date = Mar 1993 | title = Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence | url =http://dx.doi.org/10.1016/0304-3959(93)90161-h | journal = Pain | volume = 52 | issue = 3 | pages = 259–285|doi=10.1016/0304-3959(93)90161-h|issn=0304-3959|quote= | authorlink = Terence Coderre | author-link2 = Joel Katz | author-link3 = Anthony Vaccarino | author-link4 = Ronald Melzack | author-link5 = |via=}}</ref> Decades went by before this hypothesis could be corroborated by experimental research. In 1965 Mendell and Wall reported that repetitive C-fiber stimulation at low frequency results in a progressive increase of electoral discharge in cat dorsal horn neurons.<ref name=":5">{{Cite journal | last = Woolf | first = Clifford J. | date = Aug 1996 | title = Windup and central sensitization are not equivalent | url = http://dx.doi.org/10.1097/00006396-199608000-00001 | journal = Pain | volume = 66 | issue = 2 | pages = 105–108|doi=10.1097/00006396-199608000-00001|issn=0304-3959|quote= | authorlink = Clifford Woolf|via=}}</ref> They called this pattern of activity “the wind-up of a cell”.<ref>{{Cite journal | last = MENDELL| first = LORNE M. | last2 = WALL| first2 = PATRICKD. | date = Apr 1965 | title = Responses of Single Dorsal Cord Cells to Peripheral Cutaneous Unmyelinated Fibres |url =http://dx.doi.org/10.1038/206097a0 | journal = Nature | volume = 206 | issue = 4979 | pages = 97–99|doi=10.1038/206097a0|issn=0028-0836}}</ref> Though wind-up demonstrated synaptic plasticity, the changes in the neuron did not last beyond the stimulation that incited it. In 1983 [[Clifford Woolf]] and colleagues demonstrated a more lasting form of central neural plasticity.<ref>{{Cite journal | last = Woolf | first = Clifford J. | date = Dec 1983 | title = Evidence for a central component of post-injury pain hypersensitivity | url = http://dx.doi.org/10.1038/306686a0 | journal = Nature | volume = 306 | issue = 5944 | pages = 686–688|doi=10.1038/306686a0|issn=0028-0836}}</ref> After heat-induced inflammatory lesions at a rat knee joint, an enhanced responsiveness was seen in undamaged muscles surrounding the injury site. According to Woolf, "a local anesthetic block of the site of the peripheral injury did not result in collapse of the expanded receptive fields: The change was autonomous once it was triggered by the peripheral input."<ref name=":9">{{Cite journal | last = Latremoliere | first = Alban | last2 = Woolf | first2 = Clifford J. | date = Sep 2009 | title = Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity | url = http://dx.doi.org/10.1016/j.jpain.2009.06.012 | journal = The Journal of Pain | volume = 10 | issue = 9 | pages = 895–926|doi=10.1016/j.jpain.2009.06.012|issn=1526-5900|quote= | authorlink = Alban Latremoliere | author-link2 = Clifford Woolf|via=}}</ref> This provided evidence of lasting changes in excitability of the central nervous system. Referring to this phenomenon, Woolf and colleagues first used the term central sensitization in the literature in 1989.<ref name="Woolf1988">{{Cite journal | last = Woolf | first = C.J. | last2 = Thompson | first2 = S.W. | last3 = King | first3 = A.E. | date = 1988–1989 | title = Prolonged primary afferent induced alterations in dorsal horn neurones, an intracellular analysis in vivo and in vitro | url = https://www.ncbi.nlm.nih.gov/pubmed/3272296 | journal = Journal De Physiologie | volume = 83 | issue = 3 | pages = 255–266|issn=0021-7948|pmid=3272296}}</ref> In 1991, LaMotte and colleagues were the first to demonstrate central sensitization in human volunteers.<ref name="LaMotte1991">{{Cite journal | last = LaMotte | first = R.H. | last2 = Shain | first2 = C.N. | last3 = Simone | first3 = D.A. | last4 = Tsai | first4 = E.F. | date = Jul 1991 | title = Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms |url =http://dx.doi.org/10.1152/jn.1991.66.1.190 | journal = Journal of Neurophysiology | volume = 66 | issue = 1 | pages = 190–211|doi=10.1152/jn.1991.66.1.190|issn=0022-3077}}</ref> They used an injection of capsaicin, the active and painful component of chili peppers, to elicit hyperalgesia in their test subjects. Anesthetizing the region where [[capsaicin]] was injected was insufficient to block hyperalgesia. However, if the skin region was anesthetized prior to capsaicin injection, hyperalgesia does not develop.<ref name=":8" /> This clearly demonstrated it to be crucial for the development of hyperalgesia, that initial noxious input reaches the central nervous system. Once developed, however hyperalgesia became “only partially dependent on peripheral neural activity originating at the site of injury.” === Inflation of the central sensitization concept === These experiments referred to central sensitization as an activity-dependent increase in the excitability of spinal neurons. It was related to peripheral tissue damage and mostly confined to the area surrounding the site of injury.<ref name="Hansson2014">{{Cite journal | last = Hansson | first = Per | date = Oct 2014 | title = Translational aspects of central sensitization induced by primary afferent activity: What it is and what it is not | url = http://dx.doi.org/10.1016/j.pain.2014.07.016 | journal = Pain | volume = 155 | issue = 10 | pages = 1932–1934|doi=10.1016/j.pain.2014.07.016|issn=0304-3959|quote=|via=}}</ref> Though the secondary hyperalgesia it elicited lasted beyond the initial stimulus, this effect was usually short-lived and sometimes disappeared within the time-span of a day.<ref name="Woolf2011">{{Cite journal | last = Woolf | first = Clifford J. | date = Mar 2011 | title = Central sensitization: Implications for the diagnosis and treatment of pain | url =http://dx.doi.org/10.1016/j.pain.2010.09.030 | journal = Pain | volume = 152 | issue = Supplement | pages = S2–S15|doi=10.1016/j.pain.2010.09.030|issn=0304-3959}}</ref> Since then the concept of central sensitization has gone through a significant expansion.<ref name=":11">{{Cite journal | last = Gracely | first = Richard | last2 = Schweinhardt | first2 = Petra | date = 2015-07-02 | title = Programmed Symptoms: Disparate Effects United by Purpose | url =http://dx.doi.org/10.2174/1573397111666150619095125 | journal = Current Rheumatology Reviews | volume = 11 | issue = 2 | pages = 116–130|doi=10.2174/1573397111666150619095125|issn=1573-3971|quote= | authorlink = Richard Gracely | author-link2 = Petra Schweinhardt|via=}}</ref> It became widespread, lasting and unrelated to an identifiable nociceptive input form the periphery. Clifford Woolf who championed the broadening of the definition, now defines central sensitization as the “genus of all forms of pain sensitization that arise within the central nervous system”.<ref>{{Cite journal | last = Woolf | first = Clifford J. | date = Oct 2014 | title = What to call the amplification of nociceptive signals in the central nervous system that contribute to widespread pain? | url = http://dx.doi.org/10.1016/j.pain.2014.07.021 | journal = Pain | volume = 155 | issue = 10 | pages = 1911–1912|doi=10.1016/j.pain.2014.07.021|issn=0304-3959}}</ref> Woolf argues that the increase in excitability of the spinal cord he discovered in the 1980s represented only one example of what should be regarded as central sensitization. === Central sensitivity syndromes === The main rationale behind the expansion of the concept of central sensitivity came from clinical practice. Some researchers<ref>{{Cite journal | last = Yunus | first = Muhammad B. | date = Jun 2008 | title = Central Sensitivity Syndromes: A New Paradigm and Group Nosology for Fibromyalgia and Overlapping Conditions, and the Related Issue of Disease versus Illness |url =http://dx.doi.org/10.1016/j.semarthrit.2007.09.003 | journal = Seminars in Arthritis and Rheumatism | volume = 37 | issue = 6 | pages = 339–352|doi=10.1016/j.semarthrit.2007.09.003|issn=0049-0172|quote= | authorlink = Muhammad Yunus|via=}}</ref><ref>{{Cite journal | last = Toda | first = Katsuhiro | date = Jan 2012 | title = The Term of Functional Somatic Syndrome Should be Changed to the Term of Central Sensitivity Syndrome | url =http://dx.doi.org/10.1111/j.1533-2500.2011.00504.x | journal = Pain Practice | volume = 12 | issue = 1 | pages = 83–83|doi=10.1111/j.1533-2500.2011.00504.x|issn=1530-7085}}</ref> speculated that central sensitization might elucidate several of the so-called ‘[[Medically unexplained physical symptoms|medically unexplained syndromes]] (MUS)’. Not only is there a significant overlap between these syndromes, but patients who suffer from it usually have a wide array of symptoms related to chronic pain. This suggested a common, previously unrecognized mechanism involving lowered thresholds to noxious stimuli, to be behind the expression of [[Medically unexplained physical symptoms|MUS]].<ref>{{Cite journal | last = Adams | first = Leah | last2 = Turk | first2 = Dennis | date = 2015-07-02 | title = Psychosocial Factors and Central Sensitivity Syndromes |url =http://dx.doi.org/10.2174/1573397111666150619095330 | journal = Current Rheumatology Reviews | volume = 11 | issue = 2 | pages = 96–108|doi=10.2174/1573397111666150619095330|issn=1573-3971}}</ref> In 2000 Muhammad Yunus suggested to group these disorders under the unifying concept of central sensitivity syndromes (CSS).<ref name="Yunus2000JIRA">{{Cite journal | last = Yunus | first = Muhammad B. | authorlink = Muhammad Yunus | date = 2000 | url = https://www.researchgate.net/publication/284292175_Central_sensitivity_syndromes_A_unified_concept_for_fibromyalgia_and_other_similar_maladies | title = Central sensitivity syndromes: a unified concept for fibromyalgia and other similar maladies | journal = JIRA | volume = 8 | issue = | pages = 27-33}}</ref> In Yunus’ vision central sensitization could explain not only the widespread and lasting hyperalgesia these patients suffered, but also a hypersensitivity to other environmental stimuli such as [[Hyperacusis|sounds]], [[Chemical sensitivities|chemicals]] and [[Photophobia|light]]. Central sensitization was thus extended beyond the somatosensory system.<ref name=":11" />
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