Targeting A3 adenosine receptor signaling to enhance analgesia in nonresponders to spinal cord stimulation in male nerve-injured rats.

Abstract

Spinal cord stimulation (SCS) is a clinically approved therapy for neuropathic pain (NP), yet a substantial subset of patients fails to respond or shows minimal efficacy, so-called nonresponders. It remains unclear how to resolve this SCS nonresponsiveness. Using a NP model induced by tibial-sparing nerve injury (SNI-t) in male rats, we investigated whether targeting the A3 adenosine receptor (A3AR), which is enriched in microglial cells, could convert nonresponders into responders. The dose-response relationship of 2-Cl-IB-MECA (a highly selective A3AR agonist) to inhibit mechanical hypersensitivity in male SNI-t rats after intraperitoneal injection was first established by measuring the paw withdrawal thresholds. Responders and nonresponders were classified based on the degree of reduction in mechanical hypersensitivity induced by conventional SCS (50 Hz, 0.2 milliseconds, 80% motor threshold, 30 minutes). A subtherapeutic dose of 2-Cl-IB-MECA (0.3 mg/kg, intraperitoneal) was subsequently combined with either acute or repeated SCS in nonresponders. Repeated SCS reduced microglial activation but produced limited analgesia in nonresponders. Subtherapeutic-dose 2-Cl-IB-MECA by itself induced minimal pain inhibition; however, when combined with SCS, it restored analgesic responses to both acute and repeated SCS. Notably, the pain reduction from repeated SCS was accompanied by a shift toward an anti-inflammatory microglial phenotype. These findings suggest that persistent microglial activation in male SNI-t rats may contribute to SCS nonresponsiveness, and that engaging A3AR signaling represents a promising strategy to convert nonresponders into SCS responders in NP conditions.