Elucidation of Dexmedetomidine-Induced Analgesic Tolerance Mechanisms in Neuropathic Pain With Modulation of SGK1, NR2A, and NR2B Expression via the Spinal SGK1/NF-κB Signalling Pathway

Neuropathic pain (NP), resulting from nerve damage, is difficult to manage and often requires long-term treatment. However, prolonged use of pain medications can lead to addiction and reduced effectiveness over time. Understanding drug tolerance is essential for developing improved pain management strategies. Dexmedetomidine (DEX) is effective in targeting the α2-adrenergic receptor, providing relief from pain, especially NP. However, its extended use leads to tolerance and hinders its clinical utility. Herein, we investigated tolerance mechanisms and potential applications of this drug in managing NP. Adult C57BL/6 mice (male) were distributed into DEX Dosage Groups (n = 48), DEX Tolerance Model Groups (n = 32), SGK1 Inhibitor GSK650394 Groups (n = 48), and NF-κB Inhibitor PDTC Groups (n = 32) to explore dexmedetomidine's effects on NP and tolerance mechanisms. NP was established via selective ligation of the sciatic nerve branch (SNI), followed by administration of DEX. The results revealed a dose-dependent analgesic effect of DEX, with significant increases in pain thresholds observed compared to the sham group (p < 0.05). Optimal efficacy was found at a dose of 30 μg/kg, indicating its potential as an effective treatment for NP (p < 0.05). However, continuous administration of DEX over 13 days induced analgesic tolerance, evidenced by an initial increase in pain thresholds followed by a gradual decrease (p < 0.05). Despite an initial efficacy in elevating pain thresholds, the analgesic effect of DEX diminished over time, returning to pre-dose levels after 5 days (p < 0.05). Transcriptome sequencing of spinal cord samples from mice receiving multiple DEX injections revealed differential gene expression patterns, notably upregulation of SGK1, NR2A, and NR2B subunits (p < 0.05). Inhibiting SGK1 mitigated DEX-induced tolerance, suggesting its involvement in tolerance development (p < 0.05). Moreover, NF-κB inhibition reversed DEX-induced tolerance and implicated the SGK1-NF-κB pathway in the mediation of analgesic tolerance. To sum up, these findings revealed the molecular mechanism underlying DEX-induced analgesic tolerance in the NP model and offer potential avenues for future therapeutic interventions.