Given that EETs elevate cAMP [57], and that stabilization of cAMP elevates EETs we asked if the analgesic activity of rolipram, a PDE4 inhibitor, can be differentiated from that of a sEHI+ rolipram combination. Based on our previous results suggesting the involvement of neurosteroids in the mechanism of action of sEHIs [22] we used picrotoxin, an antagonist of neurosteroid action. Picrotoxin strongly antagonized the effects of sEHI+ PDEI combination but not the effects of the PDEI4 rolipram. Picrotoxin at this dose was ineffective by itself in producing changes in nociceptive thresholds. Remarkably, picrotoxin had different effects on thermal versus mechanical withdrawal responses produced by the sEHI+ PDEI combination. These findings suggest the involvement of the GABA system in the analgesic effects of the EFAs and sEHIs.
