Upregulation Of Na(V)1.7 By Endogenous Hydrogen Sulfide Contributes To Maintenance Of Neuropathic Pain

Na(v)1.7 is closely associated with neuropathic pain. Hydrogen sulfide (H2S) has recently been reported to be involved in numerous biological functions, and it has been shown that H2S can enhance the sodium current density, and inhibiting the endogenous production of H2S mediated by cystathionine beta-synthetase (CBS) using O-(carboxymethyl) hydroxylamine hemihydrochloride (AOAA) can significantly reduce the expression of Na(v)1.7 and thus the sodium current density in rat dorsal root ganglion (DRG) neurons. In the present study, it was shown that the fluorescence intensity of H2S was increased in a spared nerve injury (SNI) model and AOAA inhibited this increase. Na(v)1.7 is expressed in DRG neurons, and the expression of CBS and Na(v)1.7 were increased in DRG neurons 7, 14 and 21 days post-operation. AOAA inhibited the increase in the expression of CBS, phosphorylated (p)-MEK1/2, p-ERK1/2 and Na(v)1.7 induced by SNI, and U0126 (a MEK blocker) was able to inhibit the increase in p-MEK1/2, p-ERK1/2 and Na(v)1.7 expression. However, PF-04856264 did not inhibit the increase in CBS, p-MEK1/2, p-ERK1/2 or Na(v)1.7 expression induced by SNI surgery. The current density of Na(v)1.7 was significantly increased in the SNI model and administration of AOAA and U0126 both significantly decreased the density. In addition, AOAA, U0126 and PF-04856264 inhibited the decrease in rheobase, and the increase in action potential induced by SNI in DRG neurons. There was no significant difference in thermal withdrawal latency among each group. However, the time the animals spent with their paw lifted increased significantly following SNI, and the time the animals spent with their paw lifted decreased significantly following the administration of AOAA, U0126 and PF-04856264. In conclusion, these data show that Na(v)1.7 expression in DRG neurons is upregulated by CBS-derived endogenous H2S in an SNI model, contributing to the maintenance of neuropathic pain.