Dorsal horn DCC amplification loop induced by endplate osteoclasts generates chronic nociplastic low back pain in male mice.

Spine degeneration is associated with low back pain (LBP), a major cause of disability and functional decline. However, effective therapies for non-specific LBP remain limited because its underlying mechanisms are poorly understood. Here, we show that spine degeneration induces netrin-1 secretion in porous endplates to activate DCC signaling in dorsal root ganglion (DRG) neurons in both LBP and naturally aged male mice. Conditional loss of netrin-1 in Trap+ osteoclasts, or Dcc in Avil+ DRG neurons reduced spinal hypersensitivity. Importantly, DCC activation induces Src phosphorylation and SNARE complex docking, leading to presynaptic glutamate release in the dorsal horn (DH). Consequently, presynaptic glutamate release induces expression of both netrin-1 and DCC in DH neurons as a form of postsynaptic plasticity that initiates a positive feedback loop to amplify spinal hypersensitivity. Moreover, netrin-1/DCC expression is also amplified in the parabrachial nucleus (PBN) in the brain in both LBP and aged male mice. Thus, osteoclast-derived netrin-1 in porous endplates activates DCC-mediated hypersensitivity in DRG neurons to be further amplified in the DH neurons. These results promote the concept of non-specific LBP as a form of nociplastic pain.