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.