A potent and selective P2 × 7R antagonist ameliorates neuropathic pain by suppressing inflammation and oxidative...

Neuropathic pain is an unpleasant condition that involves neuroinflammation and oxidative stress following injury to peripheral nerves. Recently, P2 × 7R, an ATP-gated channel, has been shown to play a role in the pathogenesis of neuropathic pain. Hence, we investigated the role of a potent and selective P2 × 7R antagonist in the amelioration of neuropathic pain in a mouse model of chronic constriction injury (CCI). Mice were randomly divided into five groups, namely: sham, CCI, CCI + P2 × 7R antagonist (2.5 mg/kg), CCI + P2 × 7R antagonist (0.5 mg/kg), and CCI + pregabalin (5 mg/kg). Behavioral assessments included the open field test for locomotor activity, von Frey filaments, and hot-plate tests for assessment of mechanical and thermal hyperalgesia, respectively. Sciatic nerve and spinal cord tissue samples were analyzed for inflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB), oxidative stress markers (catalase, GSH, GST, LPO), and histopathology. It was observed that the CCI group demonstrated significantly reduced locomotor activity along with reduced thresholds for mechanical and thermal hyperalgesia compared with control animals. This was also associated with a marked increase in the expression of the pro-inflammatory cytokines, including TNF-α, IL1β, IL-6, and NF-κB in these tissues. Interestingly, repeated treatment with P2 × 7R antagonist and pregabalin significantly reversed pain behavior, along with suppression of neuroinflammation, dose- dependently. Further, P2 × 7R antagonist treatment restored BDNF, PPAR-γ levels, antioxidant defenses, and histological degenerations in sciatic nerve and spinal cord tissues. Together, these findings demonstrate that pharmacological antagonism of P2 × 7R effectively alleviates neuropathic pain related behavior while exerting potent anti-inflammatory, antioxidative, and neuroprotective actions in the CCI model.