New approaches based on topical treatments are needed for treating pain and impaired dermal blood flow. We used a topical Pluronic F127 hydrogel containing S-nitrosoglutathione (GSNO) as a prodrug to generate free NO, an effector molecule that exerts both dermal vasodilation and antinociceptive effects. GSNO-containing hydrogels underwent gelation above 12 °C and released free NO at rates that were directly dependent on the GSNO concentration in the range of 50-150 mM. The topical application of this material led to dose-response dermal vasodilation in healthy volunteers and to a reduction of up to 50 % of the hypernociception intensity in Wistar rats that were subjected to inflammatory pain. Mechanistic investigations indicated that the antinociceptive effect of the topical F127/GSNO hydrogels is produced by the local activation of the cGMP/PKG/KATP channel-signaling pathway, which was stimulated by the free NO that diffused through the skin. These results expand the scope of the biomedical applications of this material and may represent a new approach for the topical treatment of inflammatory pain.