UC San Diego

Social factors such as chronic stress are associated with mental anxiety disorders and chronic pain in young and adult humans. In rodents, the social defeat stress model (SDS) resulted in social avoidance behavior and neuronal hypersensitivity. Recently, toll-like receptor 4 (TLR4) demonstrated a crucial role in pain signaling pathways due to its link to inflammatory mediators resulting in neuronal hyperexcitability. However, the participation of TLR4 in the chronic pain development induced by SDS in mice is still poorly understood. Our work investigated the pain and anxiety behavior phenotype of juvenile mice subjected to SDS and the expression of TLR4 receptors in the spinal cord and dorsal root ganglia after stress. Male juvenile mice (C57BL6/J or TLR4-/-) underwent six physical sessions with the aggressor (CD1) and had hind paws allodynia assessed by von Frey filaments and Hargreaves test. For anxiety-like behavior evaluation, open-field and light/dark experiments were applied in all groups after SDS. TLR4 activation as measured by dimerization in dorsal root ganglia and spinal cord tissues by flow cytometry. SDS promoted chronic mechanical allodynia and thermal hyperalgesia in stressed WT animals alongside long-term body mobility changes and robust increased TLR4 activity in dorsal root ganglia macrophages and spinal cord microglia. No significant changes in behavior assessment were observed in TLR4-/- mice subjected to SDS. The results suggested that SDS in juvenile male mice promotes chronic pain phenotype and persistent body mobility impairment. These outcomes are related to the participation of TLR4 receptors, especially those expressed in immune cells of the dorsal root ganglia and spinal cord.