title: Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain.
abstract: Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, nonchannel, nonneurotransmitter therapeutic target for pain is the enzyme soluble epoxide hydrolase (sEH). The sEH degrades natural analgesic lipid mediators, epoxy fatty acids (EpFAs), therefore its inhibition stabilizes these bioactive mediators. Here we demonstrate the effects of EpFAs on diabetes induced neuropathic pain and define a previously unknown mechanism of pain, regulated by endoplasmic reticulum (ER) stress. The activation of ER stress is first quantified in the peripheral nervous system of type I diabetic rats. We demonstrate that both pain and markers of ER stress are reversed by a chemical chaperone. Next, we identify the EpFAs as upstream modulators of ER stress pathways. Chemical inducers of ER stress invariably lead to pain behavior that is reversed by a chemical chaperone and an inhibitor of sEH. The rapid occurrence of pain behavior with inducers, equally rapid reversal by blockers and natural incidence of ER stress in diabetic peripheral nervous system (PNS) argue for a major role of the ER stress pathways in regulating the excitability of the nociceptive system. Understanding the role of ER stress in generation and maintenance of pain opens routes to exploit this system for therapeutic purposes.
authors.affiliation: Department of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Nutrition Department, University of California, Davis, CA 95616;
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: Department of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Trindade da Silva
authors.affiliation: Department of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Nutrition Department, University of California, Davis, CA 95616; Department of Internal Medicine, University of California, Davis, CA 95616 bdhammock@ucdavis.edu fghaj@ucdavis.edu.
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.affiliation: Department of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616; bdhammock@ucdavis.edu fghaj@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology; D003929:Diabetic Neuropathies / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology*; D017933:Peripheral Nervous System / Q000187:drug effects / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000473:pathology; D013311:Streptozocin; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D010671:Phenylurea Compounds; D010880:Piperidines; D012333:RNA, Messenger; D014415:Tunicamycin; D013311:Streptozocin; C075773:4-phenylbutyric acid; D004851:Epoxide Hydrolases
keywords: diabetes; endoplasmic reticulum stress; pain; soluble epoxide hydrolase; tunicamycin