Biology subjects

Valmier, J.

Publications and source records attributed to Valmier, J..

5 recordsLinked to original sources

bioRxiv2026

Raf-MEK-ERK signaling mediates FLT3-induced mechanical allodynia and reduced morphine analgesic efficacy in male rodents

The cytokine FL and its receptor, Fms-like tyrosine kinase 3 (FLT3), contribute to chronic pain and to the maladaptive effects of morphine but the intracellular mechanisms underlying these effects remain incompletely understood. Here, we investigated the contribution of the Raf-MEK-ERK pathway to FLT3dependent nociceptive signaling and to the modulation of morphine analgesia. Using HEK293T cells expressing human or mouse FLT3, primary dorsal root ganglion (DRG) neurons, and rodent models, we examined ERK activation, TRPV1 sensitization, and behavioral responses following FLT3 activation by its ligand, FL. FL induced concentration-dependent ERK phosphorylation through FLT3, while pharmacological inhibition of FLT3, Raf, or MEK reduced this response. In primary DRG neurons, MEK inhibition attenuated FLinduced potentiation of capsaicin-evoked calcium responses, supporting a role for MEK-ERK signaling in TRPV1 sensitization. In vivo, intrathecal FL increased ERK phosphorylation in DRGs and induced mechanical hypersensitivity, both of which were reduced by Raf or MEK inhibition. In FLT3/MOR-expressing cells, morphine potentiated FL-induced ERK activation, an effect reduced by naloxone and abolished by FLT3 inhibition. In rats, MEK inhibition prevented the FL-induced reduction of morphine analgesia and subsequent mechanical hypersensitivity. Together, these findings identify Raf-MEK-ERK signaling as an important downstream pathway linking neuronal FLT3 activation to nociceptor sensitization and impaired morphine analgesic efficacy.

neuroscience↗

bioRxiv2025

FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice

Fms-like tyrosine kinase 3 (FLT3) plays a critical role in chronic pain through its ligand FL, a cytokine that triggers mechanical pain hypersensitivity. However, the underlying molecular mechanisms remain unclear. Here, we investigate the potential interplay between FL and IL-1{beta} a key cytokine in DRG neurons sensitization and mechanical hyperalgesia through both in vitro and in vivo approaches. ELISA assays reveal that intrathecal FL administration significantly increases IL-1{beta} protein levels in both the DRG and dorsal spinal cord of mice, beginning four hours post-injection. Using video microscopy and [Ca2+]i fluorescence imaging in primary DRG neuron cultures, we demonstrate that FL potentiation of TRPV1 receptor responses to capsaicin is partially mediated by IL-1{beta} signalling, as evidenced by a significant reduction in this potentiation in the presence of the IL-1 receptor antagonist, IL-1Ra. Furthermore, FLT3-driven acute mechanical pain hypersensitivity in vivo is reduced both by prior administration of IL-1Ra and in IL-1 receptor knockout mice. Importantly, IL-1{beta}-induced mechanical pain hypersensitivity remains independent of FLT3 signalling as shown in Flt3 knockout mice. Collectively our findings expand the understanding of neuro-immune interactions by demonstrating a potential functional link between FL/FLT3 and IL-1{beta}/IL-1R signalling in nociceptive processing. HighlightsCytokines are known to engage in complex interactions and regulate each other FL increases IL-1{beta} in DRG and DSC within 4h, but IL-1{beta} does not affect FL levels FL modulates capsaicin-induced Ca2+ influx via IL-1{beta}/IL-1R signalling in DRG neurons IL-1R inhibition delays or abolishes FL-induced mechanical hypersensitivity in vivo Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/648037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11cfa96org.highwire.dtl.DTLVardef@187ac2borg.highwire.dtl.DTLVardef@387234org.highwire.dtl.DTLVardef@1d1c058_HPS_FORMAT_FIGEXP M_FIG The timeline of the experimental design and the graphical abstract were created with BioRender.com C_FIG

neuroscience↗

bioRxiv2023

FLT3 signaling inhibition preserves opioid analgesia while abrogating tolerance and hyperalgesia

Opioid analgesia is counteracted on chronic use by tolerance and hyperalgesia inducing dose escalation and life-threatening overdoses. Mu opiate receptors (MOR) expressed in primary sensory neurons were recently found to control tolerance and hyperalgesia, but the underlying mechanisms remained elusive. Here we show that genetic inactivation of fms-like tyrosine kinase receptor 3 (FLT3) receptor in sensory neurons abrogates morphine tolerance and hyperalgesia by preventing MOR-induced hyperactivation of the cAMP signaling pathway and subsequent excitatory adaptive processes. Moreover, the specific FLT3 inhibitor BDT001 potentiates morphine analgesia in acute and chronic pain models, without aggravating morphine adverse effects, and reverses tolerance and hyperalgesia once installed. Thus, FLT3 appears as a key regulator of the MOR signaling pathway and its pharmacological blockade shows promise to enhance chronic opioid analgesic efficacy.

neuroscience↗

bioRxiv2021

Activation of peripheral neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain

Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injuryinduced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for pain chronification after peripheral nerve injury, questioning its role in the development of pain-induced mood alterations. Here, we evaluated the emotional and sensorial components of pain after a single (SI) or double paw incision (DI). We then investigated the role of FLT3 either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations. DI mice showed significant anxiodepressive-like and spontaneous pain behaviors as opposed to SI mice. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with spinal changes especially by increased microglia activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI inducedmechanical hypersensitivity in males. Repeated treatment with the microglia proliferation inhibitor GW2580 not only eliminated the exaggerated pain hypersensitivity produced by DI but also prevented anxiodepressive-related behaviors in DI animals. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a strong microglial activation while Flt3 silencing in a genetic mouse line or FLT3 blocking via functional antibodies, blunted the development of persistent pain and depression after DI. 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. The inhibition of FLT3 could thus become a promising therapy in the management of pain sensitization and related mood alterations.

neuroscience↗

bioRxiv2018

A GABAergic Maf-expressing interneuron subset regulates the speed of locomotion in Drosophila

Interneurons (INs) coordinate motoneurons activity to generate adequate patterns of muscle contractions, providing animals with the ability to adjust their body posture and to move over a range of speeds. In the Drosophila larvae several IN subtypes have been morphologically described and their function well documented. However, the general lack of molecular characterization of those INs prevents the identification of evolutionary counterparts in other model animals, limiting our understanding of widespread principles ruling neuronal circuits organization and functioning. Here we characterize a highly restricted neuronal subset expressing the Maf transcription factor Traffic Jam (TJ). We found that TJ+ neurons are highly diverse and their activation using intersectional genetics disrupted larval body posture and locomotion speed. We also showed that a small subset of TJ+ GABAergic INs, singled out by the unique expression of Per, Fkh, Grain and Hlh3b, a molecular signature reminiscent to V2b INs in vertebrate, impacted the larvae crawling speed.

neuroscience↗