Activation of neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain.
Chronic pain
FLT3
Mood disorders
Sensitization
Sensory neurons
Journal
Progress in neurobiology
ISSN: 1873-5118
Titre abrégé: Prog Neurobiol
Pays: England
ID NLM: 0370121
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
04
07
2022
revised:
16
12
2022
accepted:
12
01
2023
pubmed:
17
1
2023
medline:
3
3
2023
entrez:
16
1
2023
Statut:
ppublish
Résumé
Acute pain has been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. We demonstrated the critical role of the FLT3- tyrosine kinase receptor, expressed in sensory neurons, in pain chronification after peripheral nerve injury. However, it is unclear whether injury-induced pain sensitization can also promote long-term mood disorders. Here, we evaluated the emotional and sensorial components of pain after a single (SI) or double paw incision (DI) and the implication of FLT3. DI mice showed an anxiodepressive-like phenotype associated with extended mechanical pain hypersensitivity and spontaneous pain when compared to SI mice. Behavioral exaggeration was associated with peripheral and spinal changes including increased microglia activation after DI versus SI. Intrathecal microglial inhibitors not only eliminated the exaggerated pain hypersensitivity produced by DI but also prevented anxiodepressive-related behaviors. Behavioral and cellular changes produced by DI were blocked in Flt3 knock-out animals and recapitulated by repeated intrathecal FL injections in naive animals. Finally, humanized antibodies against FLT3 reduced DI-induced behavioral and microglia changes. Altogether our results show that the repetition of peripheral lesions facilitate not only exaggerated nociceptive behaviors but also induced anxiodepressive disorders supported by spinal central changes that can be blocked by targeting peripheral FLT3.
Identifiants
pubmed: 36646299
pii: S0301-0082(23)00005-9
doi: 10.1016/j.pneurobio.2023.102405
pii:
doi:
Substances chimiques
Flt3 protein, mouse
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102405Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest statement C.S., L.D., and J.P.L. were full-time employees at Biodol Therapeutics. J.V. is inventor of patents claiming the use of FLT3 inhibitors for the treatment of neuropathic pain and is co-founder of Biodol Therapeutics. The other authors declare no conflict of interests.