Inhibition of cystathionine β-synthetase suppresses sodium channel activities of dorsal root ganglion neurons of rats with lumbar disc herniation

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.

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats

“…In this regard, H 2 S may be acting directly on Ca V 3.2 T-type Ca 2+ channel redox sites since l -cysteine-enhanced T-current in rat sensory neurons and this effect was partially blocked by mibefradil and the oxidizing agent dinitrothiocyanobenzene [13]. In addition, H 2 S seems to sensitize P2X3 channels to produce persistent pain in a lumbar disc herniation model [16], it suppresses sustained potassium channel currents [31, 32] and increases sodium current density [33], in trigeminal and DRG neurons, respectively. Likewise, H 2 S enhances phosphorylation and expression of NMDA channels in somatic and visceral pain [34, 35], up-regulates TRPV1 channels [26] and activates TRPA1 channels in somatic and visceral pain models [25, 36–38].…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…Taken together, although various screening efforts have identified many different CBS inhibitors, for most pharmacological studies (both in vitro and in vivo) AOAA remains the compound of choice; it has been used in a large number of publications over the last decade. The basic physiological papers include mechanistic studies investigating the role of endogenous H 2 S on various channels and cellular processes (e.g., Donovan et al, 2011;Gil et al, 2011;Roy et al, 2012;Martinez-Cutillas et al, 2015;Rios et al, 2015;Xiao et al, 2015;Krause et al, 2016;Liu et al, 2016d;Rios et al, 2016;Yan et al, 2016;Yetik-Anacak et al, 2016). Many of these reports are in the area of cancer, where they show the antiproliferative effects of this compound and as additive or synergistic antitumor effects in combination with various chemotherapeutic agents (Szabo et al, 2013;Bhattacharyya et al, 2013;Módis et al, 2014b;Szczesny et al, 2016).…”

Prenatal maternal stress induces visceral hypersensitivity of adult rat offspring through activation of cystathionine-β-synthase signaling in primary sensory neurons

“…This was further supported from studies that CBS enhanced the excitability of hind paw-innervating DRG neurons via Nav1.7 channels on extrinsic afferent terminals. 16 Nav1.7 channels play an important role in chronic pain, 17 , 18 and its expression is increased in IBS models. 19 However, it is unclear whether PMS is a prenatanl factor affecting gastrointestinal sensitivity via activaiton of CBS-Nav1.7 signaling pathway in adult offspring.…”