Abstract
The pathogenesis of pain in lumbar disc herniation (LDH) remains poorly understood. We have recently demonstrated that voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons were sensitized in a rat model of LDH. However, the detailed molecular mechanism for sensitization of VGSCs remains largely unknown. This study was designed to examine roles of the endogenous hydrogen sulfide synthesizing enzyme cystathionine β-synthetase (CBS) in sensitization of VGSCs in a previously validated rat model of LDH. Here we showed that inhibition of CBS activity by O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA) significantly attenuated pain hypersensitivity in LDH rats. Administration of AOAA also reduced neuronal hyperexcitability, suppressed the sodium current density, and right-shifted the V1/2 of the inactivation curve, of hindpaw innervating DRG neurons, which is retrogradely labeled by DiI. In vitro incubation of AOAA did not alter the excitability of acutely isolated DRG neurons. Furthermore, CBS was colocalized with NaV1.7 and NaV1.8 in hindpaw-innervating DRG neurons. Treatment of AOAA markedly suppressed expression of NaV1.7 and NaV1.8 in DRGs of LDH rats. These data suggest that targeting the CBS-H2S signaling at the DRG level might represent a novel therapeutic strategy for chronic pain relief in patients with LDH.
Highlights
30 min after intrathecal injection when compared with normal saline (NS) group
We showed that administration of CBS inhibitor AOAA significantly reduced neuronal excitability, sodium current density and expression of NaV1.7 and NaV1.8 of DRGs in Lumbar disc herniation (LDH) rats
This study showed that administration of CBS inhibitor AOAA remarkably suppressed expression of NaV1.7 and NaV1.8 in DRGs of LDH rats
Summary
30 min after intrathecal injection when compared with NS group. The antinociceptive effect returned to baseline 48 hours after injection of AOAA (n = 7 rats for each group, *p < 0.01). We showed that administration of CBS inhibitor AOAA significantly reduced neuronal excitability, sodium current density and expression of NaV1.7 and NaV1.8 of DRGs in LDH rats. To determine whether AOAA treatment reverses hyperexcitability of L5-L6 DRG neurons of LDH rats, we measured cell membrane properties including resting membrane potential (RP), rheobase and the numbers of action potentials (APs) evoked by rheobase current stimulation of DiI-labeled DRG neurons (Fig. 2, arrow, bottom).
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