In addition to the peripheral anti-nociceptive effects of EFAs these molecules show central activity. Our experiments on direct spinal administration of EpDPEs to animals using the carrageenan model resulted in highly significant reduction of pain related behavior [29]. Here a dose of 3000ng of spinal EpDPEs completely reversed carrageenan induced thermal hyperalgesia while significantly reducing allodynia. These results of EFA administration are strikingly similar to our earlier studies with spinally administered sEHI where thermal hyperalgesia is reduced more effectively than mechanical allodynia. In parallel to earlier observations spinal EpDPEs had no effect on changing the thermal withdrawal latency or mechanical withdrawal thresholds on normal animals in the absence of a painful state. Overall the results indicate that the EFAs, as a class, are anti-nociceptive with both peripheral and central sites of action. These findings strongly suggest that the reduction of pain related behavior with sEHI administration is because of their ability to stabilize and elevate the levels of EFAs. Thus stabilization of the EFAs by inhibiting sEH is a potential therapeutic strategy for the treatment of pain. In fact intravenous or spinal infusion of natural EFAs with or without sEHIs could be an effective therapy for intractable and debilitating pain.
