A potential impediment to understanding the direct anti-nociceptive roles of EFAs may in fact be their strong anti-inflammatory effects. Early on we observed a lack of correlation between the anti-hyperalgesic effects and suppression of COX-2 expression [22]. This indicated an inflammation independent mechanism. Currently, convergent lines of evidence indicate the anti-nociceptive roles of sEHIs are separate from their anti-inflammatory effects. Firstly, the sEHIs are highly effective in a model of neuropathic pain that is largely independent of COX-2 induction [22]. Allodynia elicited by streptozocin induced type I diabetes is effectively blocked by structurally different sEHIs. Preliminary assessment of this activity indicates that the anti-allodynic effects are independent from modulation of glucose homeostasis in these diabetic animals, within the time frame that pain is reduced (i.e., within minutes to hours following sEHI administration). Secondly, we demonstrated direct anti-nociceptive effects of sEHIs using a pain model involving direct intraplantar administration of PGE2 [60]. Given that PGE2 is a product of both COX isozymes, the non-selective inhibitor indomethacin displays no efficacy on this type of pain [61].Consistent with these earlier findings celecoxib and
