期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 29, 页码 9082-9087出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1510137112
关键词
endoplasmic reticulum stress; pain; diabetes; tunicamycin; soluble epoxide hydrolase
资金
- US National Institute of Environmental Health Sciences (NIEHS) Grant [R01 ES002710]
- NIEHS Superfund Research Program [P42 ES004699]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R21 AR062866]
- CounterACT Program, National Institutes of Health Office
- National Institute of Neurological Disorders and Stroke (NINDS) [U54 NS079202]
- NIEHS [ES025598-01A1, 1K99ES024806]
- NIH research Grants [R01DK090492, R01DK095359, K99DK100736]
Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, non-channel, 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.
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