Importantly, all sEHIs tested to date lack a clear effect on acute pain thresholds of rodents in the absence of an induced pain state whether measured by responses to thermal or mechanical stimuli [22, 34, 55]. An unexpected property of sEHIs mediated reduction of pain emerged when injection of sequentially lower quantities of PGE2 resulted in a gradual decrease in the efficacy of a constant dose of a sEHI. Inhibitors of sEH, similar to NMDA antagonists, are effective in an activity dependent manner, requiring a baseline painful status to become anti-hyperalgesic. At high doses sEHIs induce hypoalgesia (i.e. elevation of responses above baseline measures). Based on these observations we hypothesized the presence of a pain state generated co-factor is required for the analgesic effects of sEHIs. Because PGE2 leads to the production of cAMP and activation of PKA which is a prominent molecular mechanism of inflammatory pain, we asked if cAMP would modulate the activity of sEHIs. In these experiments normal animals that did not have an underlying painful state were tested. Remarkably prevention of the degradation of cAMP by
