Soluble Epoxide Hydrolase Inhibitors and/ or Epoxyeicosatrianoic Acids Attenuate Hyperalgesia and Allodynia in a Rat Model

Analgesic compounds have wide applications for pain control in human and animal health. In mammals arachidonic acid metabolized by cytochrome P450 epoxygenases yields epoxy‐eicosatrienoic acids (EETs), which are further metabolized by a critical and unique enzyme soluble epoxide hydrolase (sEH) to the corresponding dihydroxyeicosatrienoic acids. EETs are known to be endothelium‐derived hyperpolarizing factor candidates, and can decrease inflammatory responses, along with the associated sickness behavior. We presently demonstrate that inhibition of sEH, which increases the physiological concentration of EETs, reverses behavioral hyperalgesia by as much as 69±4% in an inflammatory pain model through a poorly‐understood mechanism. We also show that delivery of exogenous EETs into the skin alone, or in combination with a sEH inhibitor produces significant analgesic effects. Thus, inhibitors of sEH, and/or EET application may represent novel treatment strategies for inflammatory conditions that cause pain and itch.