Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.
<h4>Background</h4>A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0135711 |
| _version_ | 1818835347410255872 |
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| author | Folabomi A Oladosu Matthew S Conrad Sandra C O'Buckley Naim U Rashid Gary D Slade Andrea G Nackley |
| author_facet | Folabomi A Oladosu Matthew S Conrad Sandra C O'Buckley Naim U Rashid Gary D Slade Andrea G Nackley |
| author_sort | Folabomi A Oladosu |
| collection | DOAJ |
| description | <h4>Background</h4>A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.<h4>Methods and results</h4>In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.<h4>Conclusions</h4>These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia. |
| first_indexed | 2024-12-19T02:49:16Z |
| format | Article |
| id | doaj.art-7e580d06c0b743ec90d9782e2cab2d25 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T02:49:16Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7e580d06c0b743ec90d9782e2cab2d252022-12-21T20:38:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01108e013571110.1371/journal.pone.0135711Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.Folabomi A OladosuMatthew S ConradSandra C O'BuckleyNaim U RashidGary D SladeAndrea G Nackley<h4>Background</h4>A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.<h4>Methods and results</h4>In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.<h4>Conclusions</h4>These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia.https://doi.org/10.1371/journal.pone.0135711 |
| spellingShingle | Folabomi A Oladosu Matthew S Conrad Sandra C O'Buckley Naim U Rashid Gary D Slade Andrea G Nackley Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. PLoS ONE |
| title | Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. |
| title_full | Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. |
| title_fullStr | Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. |
| title_full_unstemmed | Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. |
| title_short | Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. |
| title_sort | mu opioid splice variant mor 1k contributes to the development of opioid induced hyperalgesia |
| url | https://doi.org/10.1371/journal.pone.0135711 |
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