FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia
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.
Authors
- Maxime Thouaye
- Corinne Sonrier
- Jérôme Ruel (ORCID: https://orcid.org/0000-0003-2871-7321)
- Adrien Tassou (ORCID: https://orcid.org/0000-0003-2148-553X)
- Pierre Sokoloff (ORCID: https://orcid.org/0000-0002-7129-6043)
- François Daubeuf (ORCID: https://orcid.org/0000-0001-8061-5897)
- Myriam Antri (ORCID: https://orcid.org/0000-0002-5303-0997)
- Didier Rognan (ORCID: https://orcid.org/0000-0002-0577-641X)
- Radhouane Dallel (ORCID: https://orcid.org/0000-0001-7494-116X)
- Cyril Rivat (ORCID: https://orcid.org/0000-0002-7491-6113)
- Jean-Philippe Leyris
- Stéphanie Ventéo
- Antoine Jouvenel
- Stacy Alves
- Chamroeum Sar
- Lucie Diouloufet
- Aurore Giraudin
- Patrick Delmas (ORCID: https://orcid.org/0000-0002-0123-5413)
- Sylvie Mallié
- Jean Valmier (ORCID: https://orcid.org/0000-0002-2748-9104)
- Nelly Frossard (ORCID: https://orcid.org/0000-0002-7748-3755)
- Juliette Bertin
- Ilana Méchaly
- Patrick Carroll (ORCID: https://orcid.org/0000-0003-3287-8195)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Aix-Marseille Université (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Université Paul-Valéry Montpellier (FR)
- Laboratoire d'Innovation Thérapeutique (FR)
- Physiopathologie et pharmacologie de la douleur et de la migraine (FR)
- Institute for Neurosciences of Montpellier (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1038/s41467-024-54054-y
- Citations
- 3
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique