title: Soluble epoxide hydrolase inhibition is antinociceptive in a mouse model of diabetic neuropathy.
abstract: Neuropathic pain is currently an insufficiently treated clinical condition. There remains a critical need for efficacious therapies without severe side effects to treat the uniquely persistent and tonic pain of neuropathy. Inhibitors of the soluble epoxide hydrolase (sEH) enzyme that stabilize endogenous epoxy fatty acids have demonstrated antihyperalgesia in clinical chronic inflammatory pain and modeled neuropathic pain. Recently, the conditioned place preference assay has been used to evaluate the tonic nature of neuropathy in several animal models. The current experiments use the conditioned place preference assay alongside withdrawal thresholds to investigate the antihyperalgesic efficacy of sEH inhibitors in a murine model of diabetic neuropathy. Here, the sEH inhibitor trans-4-[4-(3-trifluoromethoxyphenyl-1-ureido)-cyclohexyloxy]-benzoic acid (t-TUCB) at 10 mg/kg induced a robust place preference in diabetic neuropathic mice representative of pain relief. Importantly, this effect was absent both in control mice and in sEH-knockout mice at the same dose, indicating that t-TUCB is not positively reinforcing or rewarding. When compared to gabapentin, t-TUCB elicited a similar degree of withdrawal threshold improvement without the same degree of spontaneous locomotion decline in neuropathic mice. Overall, these experiments show that inhibiting the sEH enzyme attenuates chronic pain and offers an alternative to current side-effect-limited therapies to meet this clinical need.
  
  
  CONCLUSIONS
  These experiments demonstrate antihyperalgesia in a murine chronic pain model mediated by inhibiting the sEH enzyme. The results of this study indicate that inhibiting the sEH is a promising alternative for blocking chronic pain.
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077206:Gabapentin; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D010671:Phenylurea Compounds / Q000097:blood / Q000494:pharmacology*; D013028:Space Perception / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D000588:Amines; D000700:Analgesics; D001565:Benzoates; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D004851:Epoxide Hydrolases
keywords: Neuropathic pain; antihyperalgesia; conditioned place preference; epoxy fatty acids; soluble epoxide hydrolase