Role of H2S in pain: Growing evidences of mystification

There have been studies suggesting the pain attenuating as well as pain inducing actions of hydrogen sulfide (H2S). Exogenous administrated H2S may be antinociceptive or pronociceptive, while the endogenous H2S is pronociceptive. Experimental studies have shown that pharmacological inhibitors of H2S biosynthetic enzymes may attenuate nociceptive as well as neuropathic pain. It suggests that nerve injury or inflammatory agents may induce the expression of H2S biosynthetic enzymes to increase the endogenous production of H2S, which acts as a pain neurotransmitter to produce pain. The endogenous H2S may act through different mechanisms including opening of T-type calcium channels, activation of voltage-gated sodium channels, suppression of potassium channels, activation of TRPA1, TRPV1 and TRPC6 channels, upregulation of spinal NMDA receptors and sensitization of purinergic receptors. Exogenous administration of H2S/precursors/donors attenuates or facilitates pain. It may be hypothesized that local administration of H2S may cause pain; while it's systemic administration may attenuate pain. The doses of H2S may also influence the pain response and H2S in low doses may contribute in reducing pain, while H2S in high doses may contribute in relieving pain. Accordingly, enzymatic inhibitors of H2S synthesis or systemic administration of slow H2S releasing agents/low dose H2S donors may be useful in attenuating nociceptive and neuropathic pain. The present review describes the dual role of H2S in pain attenuation and pain induction along with possible mechanisms.