Brain-derived neurotrophic factor in the ventrolateral orbital cortex regulates spared nerve injury-induced neuropathic pain and related emotional disorders in mice

Patients with neuropathic pain frequently experience comorbidity with anxiety and depression and lack of effective treatment. The ventrolateral orbital cortex (VLO) plays a pivotal role in regulating neuropathic pain, anxiety, and depression. Brain-derived neurotrophic factor (BDNF), abundant in the central nervous system, has increasingly been reported to play a crucial role in modulating pain, anxiety, and depression through the tyrosine kinase receptor B (TrkB). However, the role of BDNF within the VLO in the context of neuropathic pain comorbid with emotional disorders and its underlying mechanisms remains unclear. Utilizing a model of spared nerve injury (SNI) in male C57BL/6J mice, we observed a significant reduction in BDNF expression in the VLO among mice experiencing neuropathic pain coupled with anxiety-like and depression-like behaviors. Microinjection of exogenous BDNF into the VLO alleviated allodynia, anxiety-like and depression-like behaviors in SNI mice. These effects were abolished by pre-microinjection of the TrkB Antagonist ANA-12. Conversely, knocking down BDNF in the VLO of naive mice induced pain hypersensitivity along with anxiety-like and depression-like behaviors. Furthermore, overexpressing BDNF specifically in glutamatergic neurons of the VLO in SNI mice mitigated neuropathic pain and its associated emotional disturbances, but these beneficial effects were completely reversed by chemogenetic inhibition of glutamatergic neurons in the VLO. Additionally, our findings suggested the potential involvement of the BDNF-TrkB-ERK1/2-CREB signaling pathway in this process. In summary, our research highlights that BDNF alleviated the comorbidity of neuropathic pain and emotional disorders via the activation of glutamatergic neurons and the TrkB-ERK1/2-CREB signaling pathway in the VLO.

Anxiety; Brain-derived neurotrophic factor; Depression; Neuropathic pain; Ventrolateral orbital cortex.