Inhaled hydrogen sulfide prevents neuropathic pain after peripheral nerve injury in mice

Abstract

Increasing evidence suggests that the pathogenesis of neuropathic pain is mediated through activation of microglia in the spinal cord. Hydrogen sulfide attenuates microglial activation and central nervous system inflammation; however, the role of hydrogen sulfide in neuropathic pain is unclear. In this study, we examined the effects of hydrogen sulfide breathing on neuropathic pain in mice. C57BL/6J mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. After CCI, mice breathed air alone or air mixed with hydrogen sulfide at 40 ppm for 8 h on 7 consecutive days. The expression levels of inflammatory cytokines including interleukin 6 (IL-6) were measured in the spinal cord. Effects of hydrogen sulfide on IL-6-induced activation of microglia were examined in primary rat microglia. Mice that breathed air alone exhibited the neuropathic pain behavior including mechanical allodynia and thermal hyperalgesia and increased mRNA levels of IL-6 and chemokine CC motif ligand 2 (CCL2) after CCI. Inhaled hydrogen sulfide prevented the neuropathic pain behavior and attenuated the upregulation of inflammatory cytokines. Sodium sulfide inhibited IL-6-induced activation of primary microglia. These results suggest that inhaled hydrogen sulfide prevents the development of neuropathic pain in mice possibly via inhibition of the activation of microglia in the spinal cord.

Neonatal Colonic Inflammation Increases Spinal Transmission and Cystathionine β-Synthetase Expression in Spinal Dorsal Horn of Rats with Visceral Hypersensitivity

“…The H 2 S donor Na 2 S was reported to activate the mu-opioid receptor MOR ( Syhr et al, 2015 ). The inhibition of NF-κB by H 2 S could inhibit microglial activation, thus preventing the development of neuropathic pain ( Kida et al, 2015 ). ATF3 and expression of pCREB can be inhibited by H 2 S in the SC to alleviate chronic neuropathic pain ( Lin et al, 2014 ; Kida et al, 2015 ).…”

Effects of natural and synthetic isothiocyanate-based H 2 S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels

“…Nonetheless, several studies have suggested significant pain relieving effects of H 2 S donors against neuropathic and visceral pain (Distrutti et al, 2006;Lin et al, 2014;Kida et al, 2015). Recently, some isothiocyanate derivatives, slow releasing H 2 Sdonor moieties, and NaHS, a prototypical H 2 S-generating agent, were described as activators of Kv7 potassium channels (Testai et al, 2015;Martelli et al, 2013a), a class of the voltage-gated potassium channels which plays a pivotal role in pain modulation (Zheng et al, 2013;Busserolles et al, 2016).…”

Gasotransmitters in Vascular Complications of Diabetes

“…Conversely, antinociceptive effects also have been reported for H 2 S. These effects were antagonized by the ATP-sensitive potassium (K ATP ) channel blocker glibenclamide and by NOS inhibition (103). Inhalation of H 2 S reduced the development of neuropathic pain by reducing the resulting increase in interleukin-6 and chemokines, which was attributed to an inhibition of microglia activation in course of neuropathy (104). Furthermore, H 2 S functions as a neuroprotective agent by enhancing the production of glutathione, a major intracellular antioxidant that scavenges mitochondrial ROS (105).…”