The covalent linking of nonsteroidal anti-inflammatory drugs (NSAIDs) to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increasing anti-inflammatory and analgesic potency. We tested the hypothesis that a H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. ATB-352 was significantly more potent and effective as an analgesic than ketoprofen, and did not elicit GI damage. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352.

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