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

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Title: Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain.
Authors: Inceoglu, Bora1, Bettaieb, Ahmed2, Trindade da Silva, Carlos A.1, Lee, Kin Sing Stephen1, Haj, Fawaz G.2,3 fghaj@ucdavis.edu, Hammock, Bruce D.1 bdhammock@ucdavis.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 7/21/2015, Vol. 112 Issue 29, p9082-9087. 6p.
Subjects: Endoplasmic reticulum, Peripheral nervous system, Therapeutics, Epoxide hydrolase, Analgesia
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, 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. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain.
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  Data: <searchLink fieldCode="AR" term="%22Inceoglu%2C+Bora%22">Inceoglu, Bora</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Bettaieb%2C+Ahmed%22">Bettaieb, Ahmed</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Trindade+da+Silva%2C+Carlos+A%2E%22">Trindade da Silva, Carlos A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lee%2C+Kin+Sing+Stephen%22">Lee, Kin Sing Stephen</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Haj%2C+Fawaz+G%2E%22">Haj, Fawaz G.</searchLink><relatesTo>2,3</relatesTo><i> fghaj@ucdavis.edu</i><br /><searchLink fieldCode="AR" term="%22Hammock%2C+Bruce+D%2E%22">Hammock, Bruce D.</searchLink><relatesTo>1</relatesTo><i> bdhammock@ucdavis.edu</i>
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  Data: <searchLink fieldCode="DE" term="%22Endoplasmic+reticulum%22">Endoplasmic reticulum</searchLink><br /><searchLink fieldCode="DE" term="%22Peripheral+nervous+system%22">Peripheral nervous system</searchLink><br /><searchLink fieldCode="DE" term="%22Therapeutics%22">Therapeutics</searchLink><br /><searchLink fieldCode="DE" term="%22Epoxide+hydrolase%22">Epoxide hydrolase</searchLink><br /><searchLink fieldCode="DE" term="%22Analgesia%22">Analgesia</searchLink>
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.1510137112
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        Text: English
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