The YING and YANG of H2S Signaling in Nociception and Disease
Guang Yin Xu
Institute of Neuroscience, Soochow University
Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. Hydrogen sulfide (H2S), an endogenous gaseotransmitter/modulator, is becoming appreciated that it may be involved in a wide variety of processes including inflammation and nociception.Recent studies have indicated that H2S produced both neurotoxicity and neuroprotection in central nervous system, evoked contraction and relaxation of smooth muscle cells, and produced antinociception and pro-nociceptive effect.The aim of this study was to investigate the role and molecular mechanisms for H2S signaling in peripheral nociceptive processing.We showed here that expression of H2S synthesizing enzyme cystathionine-beta-synthetase (CBS) was significantly upregulated in a rat model of arthritis induced by complete Freud adjuvant (CFA).The CFA-evoked mechanical hyperalgesia was attenuated by CBS inhibitors, hydroxylamine (HA) and AOAA, in a dose-dependent manner.Pretreatment with AOAA significantly delayed the onset of mechanical hyperalgesia induced by CFA injection.Intraplantar administration of NaHS or L-cysteine elicited mechanical hyperalgesia, in a dose- and time-dependent fashion, in healthy rats.In patch-clamp studies, dorsal root ganglion (DRG) neurons are hyperexcitable after CFA injection.AOAA pretreatment normalized the neuronal excitability.NaHS in vitro application enhanced the excitability of DRG neurons isolated from healthy rats.Furthermore, NaHS application led to a significant increase in TTX-resistant sodium current density (PRE: 160.6±14.1 pA/pF, POST 194.3±37.6 pA/pF, n=6, P<0.05).These data together with our previous report that CBS-H2S signaling plays a pivotal role in the visceral hypersensitivity suggest that H2S appears to function as a novel nociceptive messenger through sensitization of voltage-gated sodium channels in DRG neurons, particularly during peripheral inflammation, thus leading to sensitization of nociceptive processing and hyperalgesia.A greater understanding of the role of hydrogen sulfide in modulating nociceptive processes may potentially lead to development of novel targets for improving analgesia.