Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain
Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. 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 initi...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2014-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/02370 |
| _version_ | 1811200113046978560 |
|---|---|
| author | Stéphanie Ratté Yi Zhu Kwan Yeop Lee Steven A Prescott |
| author_facet | Stéphanie Ratté Yi Zhu Kwan Yeop Lee Steven A Prescott |
| author_sort | Stéphanie Ratté |
| collection | DOAJ |
| description | Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. 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 naïve 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. |
| first_indexed | 2024-04-12T01:59:20Z |
| format | Article |
| id | doaj.art-8396a9069dc844538e14608ecc37401e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:59:20Z |
| publishDate | 2014-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8396a9069dc844538e14608ecc37401e2022-12-22T03:52:43ZengeLife Sciences Publications LtdeLife2050-084X2014-04-01310.7554/eLife.02370Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic painStéphanie Ratté0Yi Zhu1Kwan Yeop Lee2Steven A Prescott3Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, United StatesPittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, United StatesNeurosciences and Mental Health, The Hospital for Sick Children, Toronto, CanadaNeurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, United StatesNeuropathic pain remains notoriously difficult to treat despite numerous drug targets. 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 naïve 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.https://elifesciences.org/articles/02370neuropathic paindegeneracyexcitabilitymembrane potential oscillationdynamic clampbursting |
| spellingShingle | Stéphanie Ratté Yi Zhu Kwan Yeop Lee Steven A Prescott Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain eLife neuropathic pain degeneracy excitability membrane potential oscillation dynamic clamp bursting |
| title | Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain |
| title_full | Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain |
| title_fullStr | Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain |
| title_full_unstemmed | Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain |
| title_short | Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain |
| title_sort | criticality and degeneracy in injury induced changes in primary afferent excitability and the implications for neuropathic pain |
| topic | neuropathic pain degeneracy excitability membrane potential oscillation dynamic clamp bursting |
| url | https://elifesciences.org/articles/02370 |
| work_keys_str_mv | AT stephanieratte criticalityanddegeneracyininjuryinducedchangesinprimaryafferentexcitabilityandtheimplicationsforneuropathicpain AT yizhu criticalityanddegeneracyininjuryinducedchangesinprimaryafferentexcitabilityandtheimplicationsforneuropathicpain AT kwanyeoplee criticalityanddegeneracyininjuryinducedchangesinprimaryafferentexcitabilityandtheimplicationsforneuropathicpain AT stevenaprescott criticalityanddegeneracyininjuryinducedchangesinprimaryafferentexcitabilityandtheimplicationsforneuropathicpain |