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

Abstract

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.