Soluble Epoxide Hydrolase Inhibitors are Orally Available, Non Opiate, Non NSAID Analgesics which Block Neuropathic Pain Better than Gabapentin or Pregabalin without Reduction in Mobility or Cognition

Epoxy fatty acids (EPFA) are known chemical mediators, and they are regulated by both biosynthesis and by hydrolysis to their corresponding diols by the soluble epoxide hydrolase (sEH). A new series of orally available chemicals act as transition state mimics to inhibit the sEH at low picomolar concentrations and increase circulating titers of EPFA. In particular regioisomeric epoxides of ARA and DHA reduce nociception in a variety of rodent assays, and their action is enhanced with sEH inhibitors. Following oral, IV or topical administration, sEH inhibitors directly reduce inflammatory and neuropathic pain perception in rodent, canine, feline and equine systems. Good PK‐ADME has been demonstrated in these species and in non – human primates. In the operant conditioned place preference assay, sEH inhibitors are far more potent than gabapentin in the murine diabetic neuropathic pain model. In the rat sEH have also displayed better potency and longer duration of action than either gabapentin or pregabalin. The sEH inhibitors do not alter mobility or coordination in open field and rotorod assays even at higher than therapeutic doses, either alone or when combined with NSAIDs. The sEH inhibitors reduce the pain associated with opiate withdrawal and do not display reward based behaviors as seen in addiction. Thus the compounds appear promising non opiate, non NSAID compounds which reduce inflammation as well as the perception of inflammatory and neuropathic pain. In addition the sEH inhibitors synergize dramatically with NSAIDs, extend NSAID beneficial effects in reducing neuropathic pain while reducing their gastrointestinal and cardiovascular side effects. The sEH inhibitors and the corresponding EPFA they stabilize influence a variety of biological processes acting largely in opposition to the better studied and predominantly proinflammatory mediators in the COX and LOX branches of the arachidonic acid cascade. It appears that the blocking of the endoplasmic reticulum stress response by EPFA is a common mechanism for the action of sEH inhibitors among these multiple and largely beneficial biological responses. The antinociceptive effects of EPFA seem mediated by an additional GABAergic mechanism, possibly through modulating neurosteroid synthesis. Inhibitors of steroid synthesis strongly block the antinociceptive effects and the EPFA selectively delay GABA antagonist induced seizures when administered into the brain. Likewise sEH inhibitors display anti‐convulsant effects and in sEH null mice these effects are recapitulated suggesting a central component to their activity profile. A signaling cascade regulated by cAMP seems to be affected by EPFA since co‐inhibition of phosphodiesterase 4 isozyme greatly enhances the antinociceptive efficacy of sEH inhibitors. Support or Funding Information NIEHS R01 ES002710, NIEHS/Superfund P42 ES004699, NIH/NIDDK U24 DK097154, NIDDK R01DK090492, AB is suppored by 1K99DK100736‐01 and KW is supported by 5 T32L086350‐08.