Voltage-gated sodium channel 1.8 contributes to hyperalgesia induced by the coexistence of anxiety and remifentanil exposure
Abstract
Background: Remifentanil-induced hyperalgesia (RIH) is directly mediated by altered mitochondrial dynamics.Moreover, anxiety is proven to worsen hyperalgesia.Voltage-gated sodium channel 1.8 (NaV1.8) is involved in both nociceptive initiation and anxiety.However, its role in modulating RIH, particularly in the coexistence of anxiety and RIH (CARIH), remains unexplored.Methods: A total of 148 Sprague-Dawley male rats were used to explore whether silencing NaV1.8 activation could alleviate CARIH.The behavioral effects were assessed using the open field, novelty suppressed feeding, and paw withdrawal tests.The mechanisms of antisense oligodeoxynucleotides (AS-ODN) targeting NaV1.8 (AS-NaV1.8)were investigated through western blot, RT-qPCR, electron microscopy, mitochondrial superoxide imaging, glutathione (GSH/GSSG) ratio, and malondialdehyde measurement.Results: NaV1.8 was upregulated at the mRNA level in the dorsal root ganglia (DRG) (P < 0.001) after CARIH.Meanwhile, spinal NR 2 B and Drp1 began to increase at 4 hours (P = 0.021) and 24 hours (P < 0.001), respectively.AS-NaV1.8 decreased spinal NR 2 B and Drp1 levels (P < 0.01), while increasing Mfn2 and OPA1 expression (P < 0.01).The MitoSox-positive cells in Group AS (AS-NaV1.8injected into rats with CARIH) were fewer than those in Group AR (CARIH group) (P = 0.013) and Group MM (mismatch-ODN of NaV1.8 injected into rats with CARIH) (P = 0.018).Abnormal fission of spinal mitochondria was reduced in Group AS compared to…
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