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

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 reca-pitulated 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 pe-ripheral 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.

Automated summary

Acute pain can lead to chronic pain, and the FLT3-tyrosine kinase receptor plays a crucial role in pain chronification after peripheral nerve injury. This study aimed to investigate whether injury-induced pain sensitization can also contribute to long-term mood disorders. The results showed that mice with double paw incisions exhibited an anxiodepressive-like phenotype and increased pain sensitivity compared to those with single incisions. These behavioral changes were associated with peripheral and spinal changes, including increased microglia activation. Blocking FLT3 and microglia activation alleviated the exaggerated pain sensitivity and anxiodepressive behaviors induced by double incisions. Humanized antibodies against FLT3 also reduced behavioral and microglia changes. Overall, this study suggests that peripheral lesions can not only cause exaggerated pain behaviors but also induce anxiodepressive disorders, and targeting peripheral FLT3 may provide a potential therapeutic approach.