FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia

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 () and Cyril Rivat ()
Additional contact information
Antoine Jouvenel: Université de Montpellier
Adrien Tassou: Université de Montpellier
Maxime Thouaye: Université de Montpellier
Jérôme Ruel: Aix-Marseille Université - INSERM 1263 -INRAE 1260
Myriam Antri: NeuroDol INSERM 1107
Jean-Philippe Leyris: Biodol Therapeutics
Aurore Giraudin: NeuroDol INSERM 1107
Sylvie Mallié: Institut des Neurosciences de Montpellier
Chamroeum Sar: Université de Montpellier
Lucie Diouloufet: Institut des Neurosciences de Montpellier
Corinne Sonrier: Institut des Neurosciences de Montpellier
François Daubeuf: UMR7200 CNRS/Université de Strasbourg
Juliette Bertin: Institut des Neurosciences de Montpellier
Stacy Alves: Université de Montpellier
Stéphanie Ventéo: Université de Montpellier
Nelly Frossard: UMR7200 CNRS/Université de Strasbourg
Patrick Carroll: Université de Montpellier
Ilana Mechaly: Université de Montpellier
Didier Rognan: UMR7200 CNRS/Université de Strasbourg
Pierre Sokoloff: Biodol Therapeutics
Radhouane Dallel: NeuroDol INSERM 1107
Patrick Delmas: Aix-Marseille Université - INSERM 1263 -INRAE 1260
Jean Valmier: Université de Montpellier
Cyril Rivat: Université de Montpellier

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54054-y

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