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Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and\/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from na\u00efve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels.<\/jats:p>","DOI":"10.7554\/elife.02370","type":"journal-article","created":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T11:57:15Z","timestamp":1396353435000},"source":"Crossref","is-referenced-by-count":57,"title":["Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain"],"prefix":"10.7554","volume":"3","author":[{"given":"St\u00e9phanie","family":"Ratt\u00e9","sequence":"first","affiliation":[{"name":"Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, Canada"},{"name":"Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Pittsburgh 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