Small proline-rich repeat protein 1A-mediated ephrin-A5 downregulation drives neuropathic pain via brain-derived neurotrophic factor/Tropomyosin receptor kinase B signaling.

Neuropathic pain is a common chronic pain condition that severely impacts patients' quality of life. While Small proline-rich protein 1A (SPRR1A) is a well-known marker for axonal regeneration, its specific role and the underlying molecular mechanisms in neuropathic pain remain elusive. The present study demonstrates that SPRR1A is significantly increased in the spinal dorsal horn of spared nerve injury (SNI) mice, accompanied by ephrin-A5 downregulation, activation of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway, and enhanced neuronal excitability. SPRR1A overexpression induces allodynia in naïve mice, whereas knockdown of SPRR1A alleviates hyperalgesia and reduces neuronal hyperactivity. Silencing SPRR1A restores ephrin-A5 expression and suppresses BDNF/TrkB activation. Co-immunoprecipitation confirms that SPRR1A interacts with ephrin-A5, while ephrin-A5 competitively binds TrkB to block BDNF-mediated signaling. Conversely, SPRR1A overexpression decreases ephrin-A5 level and facilitates BDNF/TrkB activation. Ephrin-A5 siRNA reverses the inhibitory effects of SPRR1A knockdown on TrkB signaling. Furthermore, intrathecal administration of recombinant ephrin-A5 significantly attenuates hyperalgesia in SNI mice. Together, these findings identify SPRR1A as a key mediator of neuropathic pain that promotes central sensitization by suppressing ephrin-A5, thereby enhancing BDNF/TrkB signaling in the spinal dorsal horn. Targeting the SPRR1A-ephrin-A5-BDNF/TrkB axis may represent a promising therapeutic strategy for neuropathic pain management.