Therapies to treat chronic neuropathic pain and its associated comorbidities are limited. Recent studies demonstrated that the administration of slow-releasing hydrogen sulfide (HS) donors inhibited chemotherapy-induced neuropathic pain. However, the antidepressant or anxiolytic effects of these compounds and their mechanisms of action during chronic neuropathic pain have not been evaluated.To determine whether the administration of two slow-releasing HS donors, allyl isothiocyanate (A-ITC) and phenyl isothiocyanate (P-ITC), inhibits the nociceptive and emotional disorders associated with chronic neuropathic pain.In C57BL/6 male mice with neuropathic pain caused by the chronic constriction of the sciatic nerve, we assessed the effects of intraperitoneal administration of A-ITC and P-ITC in (a) the mechanical allodynia, thermal hyperalgesia and thermal allodynia induced by nerve ligation; (b) the anxiety- and depressive-like behaviours linked with neuropathic pain; (c) glial activation and mitogen-activated protein kinases phosphorylation, and (d) expression of the antioxidant enzymes, heme oxygenase 1 (HO-1), NADPH quinone oxidoreductase1, and glutathione S-transferase mu-1 (GSTM1), and alpha-1 (GSTA1), in hippocampus and prefrontal cortex (PFC).Both treatments inhibited the allodynia and hyperalgesia, depressive-like behaviours, astroglial activation, and the extracellular signal-regulated kinase 1/2 phosphorylation but were unable to abolish the anxiety-like behaviours accompanying neuropathic pain. A-ITC and P-ITC also augmented the expression of HO-1, GSTM1, and GSTA1 in the hippocampus and/or PFC.The administration of slow-releasing HS donors might be a promising treatment for the management of chronic neuropathic pain and some associated comorbidities via inhibiting the inflammatory and plasticity changes, and activating the endogenous antioxidant responses.