Idioma:

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Inceoglu, Bora ; Ahmed Bettaieb ; Carlos A. Trindade da Silva ; Kin Sing Stephen Lee ; Fawaz G. Haj ; Bruce D. Hammock

Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.9082-9087 [Periódico revisado por pares]

United States: National Academy of Sciences

Texto completo disponível

Citações Citado por

Enviar para

Título:
Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain
Autor: Inceoglu, Bora ; Ahmed Bettaieb ; Carlos A. Trindade da Silva ; Kin Sing Stephen Lee ; Fawaz G. Haj ; Bruce D. Hammock
Assuntos: analgesics ; Animals ; Apoptosis - drug effects ; Apoptosis - genetics ; Autophagy - drug effects ; Autophagy - genetics ; Biological Sciences ; Blood Glucose - metabolism ; Blotting, Western ; Diabetes ; Diabetes Mellitus, Experimental - blood ; Diabetes Mellitus, Experimental - cerebrospinal fluid ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - pathology ; Diabetic Neuropathies - blood ; Diabetic Neuropathies - cerebrospinal fluid ; Diabetic Neuropathies - drug therapy ; Diabetic Neuropathies - pathology ; endoplasmic reticulum ; endoplasmic reticulum stress ; Endoplasmic Reticulum Stress - drug effects ; Endoplasmic Reticulum Stress - genetics ; Enzyme Inhibitors - pharmacology ; Epoxide Hydrolases - antagonists & inhibitors ; Epoxide Hydrolases - metabolism ; Fatty acids ; ion channels ; Lipids ; Male ; Nervous system ; Neuralgia - blood ; Neuralgia - cerebrospinal fluid ; Neuralgia - drug therapy ; Neuralgia - pathology ; pain ; Pain management ; peripheral nervous system ; Peripheral Nervous System - drug effects ; Peripheral Nervous System - pathology ; phenotype ; Phenylbutyrates - pharmacology ; Phenylurea Compounds - pharmacology ; Piperidines - pharmacology ; Rats, Sprague-Dawley ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; signal transduction ; Skin - pathology ; soluble epoxide hydrolase ; Streptozocin ; therapeutics ; tunicamycin ; Tunicamycin - pharmacology
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.9082-9087
Notas: http://dx.doi.org/10.1073/pnas.1510137112
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Contributed by Bruce D. Hammock, June 1, 2015 (sent for review January 9, 2015; reviewed by Andrea G Hohmann and Daniele Piomelli)
1B.I. and A.B. contributed equally to this work.
Author contributions: B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. designed research; B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. performed research; A.B., K.S.S.L., F.G.H., and B.D.H. contributed new reagents/analytic tools; B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. analyzed data; and B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. wrote the paper.
Reviewers: A.G.H., Indiana University; and D.P., University of California, Irvine.
Descrição: 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. Here we define the causative role of endoplasmic reticulum (ER) stress on selective modulation of pain signaling. High levels of ER stress and neuropathic pain in diabetic animals are reduced using ER stress blockers. In healthy animals, turning on the ER stress signal transduction cascade generates an immediate but lasting and site restricted painful phenotype, which is reversible by ER stress blockers. This previously unnoticed mechanism explains the broad lack of efficacy of available analgesics and should ignite the discovery of a new generation of therapeutics that do not directly quell ion channel or neurotransmitter activity.
Editor: United States: National Academy of Sciences
Idioma: Inglês

Links

View this record in MEDLINE/PubMed

Voltar para lista de resultados

Realização: Logos de Redes Sociais:

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Inceoglu, Bora ; Ahmed Bettaieb ; Carlos A. Trindade da Silva ; Kin Sing Stephen Lee ; Fawaz G. Haj ; Bruce D. Hammock

United States: National Academy of Sciences

Buscando em bases de dados remotas. Favor aguardar.