FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia
Abstract Navigating the duality of opioids’ potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to med...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54054-y |
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| author | Antoine Jouvenel Adrien Tassou Maxime Thouaye Jérôme Ruel Myriam Antri Jean-Philippe Leyris Aurore Giraudin Sylvie Mallié Chamroeum Sar Lucie Diouloufet Corinne Sonrier François Daubeuf Juliette Bertin Stacy Alves Stéphanie Ventéo Nelly Frossard Patrick Carroll Ilana Mechaly Didier Rognan Pierre Sokoloff Radhouane Dallel Patrick Delmas Jean Valmier Cyril Rivat |
| author_facet | Antoine Jouvenel Adrien Tassou Maxime Thouaye Jérôme Ruel Myriam Antri Jean-Philippe Leyris Aurore Giraudin Sylvie Mallié Chamroeum Sar Lucie Diouloufet Corinne Sonrier François Daubeuf Juliette Bertin Stacy Alves Stéphanie Ventéo Nelly Frossard Patrick Carroll Ilana Mechaly Didier Rognan Pierre Sokoloff Radhouane Dallel Patrick Delmas Jean Valmier Cyril Rivat |
| author_sort | Antoine Jouvenel |
| collection | DOAJ |
| description | Abstract Navigating the duality of opioids’ potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model. We found that chronic morphine treatment increases FLT3 and MOR co-expression, and that inhibiting FLT3 represses MOR-induced hyperactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway, mitigating maladaptive excitatory processes engaged after chronic morphine treatment. Furthermore, in postsurgical or inflammatory models of chronic pain, co-administering morphine with a FLT3-specific inhibitor not only prevents or suppresses tolerance and hyperalgesia but also potentiates the analgesic efficacy of morphine, without aggravating other morphine-induced adverse effects. Our findings suggest that pairing morphine with FLT3 inhibitors could become a promising avenue for chronic pain management to safely harness the power of opioids, without the risk of dose escalation. By enhancing morphine analgesic potency through FLT3 inhibition, this approach could minimize opioid dosage, thereby curtailing the risk of addiction and other opioid-related side effects. |
| format | Article |
| id | doaj-art-62199c8ab61a47228dbb08f3a3507de8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-62199c8ab61a47228dbb08f3a3507de82024-11-10T12:33:34ZengNature PortfolioNature Communications2041-17232024-11-0115111510.1038/s41467-024-54054-yFLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesiaAntoine Jouvenel0Adrien Tassou1Maxime Thouaye2Jérôme Ruel3Myriam Antri4Jean-Philippe Leyris5Aurore Giraudin6Sylvie Mallié7Chamroeum Sar8Lucie Diouloufet9Corinne Sonrier10François Daubeuf11Juliette Bertin12Stacy Alves13Stéphanie Ventéo14Nelly Frossard15Patrick Carroll16Ilana Mechaly17Didier Rognan18Pierre Sokoloff19Radhouane Dallel20Patrick Delmas21Jean Valmier22Cyril Rivat23Université de MontpellierUniversité de MontpellierUniversité de MontpellierCentre de Recherche en CardioVasculaire et Nutrition, Aix-Marseille Université - INSERM 1263 -INRAE 1260NeuroDol INSERM 1107Biodol TherapeuticsNeuroDol INSERM 1107Inserm U−1298, Institut des Neurosciences de MontpellierUniversité de MontpellierInserm U−1298, Institut des Neurosciences de MontpellierInserm U−1298, Institut des Neurosciences de MontpellierLaboratoire d’Innovation Thérapeutique, UMR7200 CNRS/Université de StrasbourgInserm U−1298, Institut des Neurosciences de MontpellierUniversité de MontpellierUniversité de MontpellierLaboratoire d’Innovation Thérapeutique, UMR7200 CNRS/Université de StrasbourgUniversité de MontpellierUniversité de MontpellierLaboratoire d’Innovation Thérapeutique, UMR7200 CNRS/Université de StrasbourgBiodol TherapeuticsNeuroDol INSERM 1107Centre de Recherche en CardioVasculaire et Nutrition, Aix-Marseille Université - INSERM 1263 -INRAE 1260Université de MontpellierUniversité de MontpellierAbstract Navigating the duality of opioids’ potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model. We found that chronic morphine treatment increases FLT3 and MOR co-expression, and that inhibiting FLT3 represses MOR-induced hyperactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway, mitigating maladaptive excitatory processes engaged after chronic morphine treatment. Furthermore, in postsurgical or inflammatory models of chronic pain, co-administering morphine with a FLT3-specific inhibitor not only prevents or suppresses tolerance and hyperalgesia but also potentiates the analgesic efficacy of morphine, without aggravating other morphine-induced adverse effects. Our findings suggest that pairing morphine with FLT3 inhibitors could become a promising avenue for chronic pain management to safely harness the power of opioids, without the risk of dose escalation. By enhancing morphine analgesic potency through FLT3 inhibition, this approach could minimize opioid dosage, thereby curtailing the risk of addiction and other opioid-related side effects.https://doi.org/10.1038/s41467-024-54054-y |
| spellingShingle | Antoine Jouvenel Adrien Tassou Maxime Thouaye Jérôme Ruel Myriam Antri Jean-Philippe Leyris Aurore Giraudin Sylvie Mallié Chamroeum Sar Lucie Diouloufet Corinne Sonrier François Daubeuf Juliette Bertin Stacy Alves Stéphanie Ventéo Nelly Frossard Patrick Carroll Ilana Mechaly Didier Rognan Pierre Sokoloff Radhouane Dallel Patrick Delmas Jean Valmier Cyril Rivat FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia Nature Communications |
| title | FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| title_full | FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| title_fullStr | FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| title_full_unstemmed | FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| title_short | FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| title_sort | flt3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia |
| url | https://doi.org/10.1038/s41467-024-54054-y |
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