Structural changes in the nociceptive system induced by long-term conventional spinal cord stimulation in experimental painful diabetic polyneuropathy

Background Clinical studies suggest that long-term conventional spinal cord stimulation (LT-SCS) for painful diabetic peripheral neuropathy (PDPN) is initially effective but may decline in efficacy over time. Preclinical studies indicate that LT-SCS alleviates mechanical hypersensitivity and enhances hind paw blood flow in PDPN rats, suggesting nociceptive system plasticity. This study hypothesized that LT-SCS induces peripheral hind paw small-fiber sprouting and reduces central protein expression of glial and P2X4 brain-derived neurotrophic factor (BDNF) pathway markers.Methods Diabetes was induced via Streptozotocin injection in 32 rats, with 16 developing PDPN and receiving a quadrupolar lead implant. LT-SCS was applied for 4 weeks, 12 hours per day. Pain behavior was assessed using the Von Frey test for mechanical hypersensitivity and the mechanical conflict avoidance system for motivational aspects of pain. Fiber sprouting was assessed via immunohistochemical analysis of nerve fibers in the hind paw skin. Protein expression in the spinal cord was assessed using western blotting.Results LT-SCS increased the baseline threshold of mechanical hypersensitivity in PDPN animals, consistent with previous findings, but showed no effects on motivational aspects of pain. Hind paw tissue analysis revealed significantly increased intraepidermal nerve fiber density of PGP9.5 fibers in LT-SCS animals compared with Sham-SCS animals. Protein analysis showed significantly decreased pro-BDNF expression in LT-SCS animals compared with Sham-SCS animals.Conclusion LT-SCS induces structural changes in both peripheral and central components of the nociceptive system in PDPN animals. These changes may contribute to observed behavioral modifications, elucidating mechanisms underlying LT-SCS efficacy in PDPN management.