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Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous syste...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259992/ https://www.ncbi.nlm.nih.gov/pubmed/25386959 http://dx.doi.org/10.1038/tp.2014.121 |
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author | Johnson, J L Rolan, P E Johnson, M E Bobrovskaya, L Williams, D B Johnson, K Tuke, J Hutchinson, M R |
author_facet | Johnson, J L Rolan, P E Johnson, M E Bobrovskaya, L Williams, D B Johnson, K Tuke, J Hutchinson, M R |
author_sort | Johnson, J L |
collection | PubMed |
description | Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(−1)), morphine (20 mg kg(−1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (−9.5 s, P<0.01 and −7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity—although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement. |
format | Online Article Text |
id | pubmed-4259992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-42599922014-12-12 Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation Johnson, J L Rolan, P E Johnson, M E Bobrovskaya, L Williams, D B Johnson, K Tuke, J Hutchinson, M R Transl Psychiatry Original Article Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(−1)), morphine (20 mg kg(−1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (−9.5 s, P<0.01 and −7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity—although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement. Nature Publishing Group 2014-11 2014-11-11 /pmc/articles/PMC4259992/ /pubmed/25386959 http://dx.doi.org/10.1038/tp.2014.121 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Johnson, J L Rolan, P E Johnson, M E Bobrovskaya, L Williams, D B Johnson, K Tuke, J Hutchinson, M R Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title | Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title_full | Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title_fullStr | Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title_full_unstemmed | Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title_short | Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
title_sort | codeine-induced hyperalgesia and allodynia: investigating the role of glial activation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259992/ https://www.ncbi.nlm.nih.gov/pubmed/25386959 http://dx.doi.org/10.1038/tp.2014.121 |
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