Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

Persistent Link:
http://hdl.handle.net/10150/610215
Title:
Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain
Author:
Tillu, Dipti; Melemedjian, Ohannes; Asiedu, Marina; Qu, Ning; De Felice, Milena; Dussor, Gregory; Price, Theodore
Affiliation:
Department of Pharmacology, University of Arizona, 1501 N Campbell Ave, PO BOX 245050, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, USA; Bio5 Institute, University of Arizona, Tucson, USA
Issue Date:
2012
Publisher:
BioMed Central
Citation:
Tillu et al. Molecular Pain 2012, 8:5 http://www.molecularpain.com/content/8/1/5
Journal:
Molecular Pain
Rights:
© 2012 Tillu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.RESULTS:To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.CONCLUSIONS:These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.
EISSN:
1744-8069
DOI:
10.1186/1744-8069-8-5
Version:
Final published version
Additional Links:
http://mpx.sagepub.com/content/8/1744-8069-8-5.full

Full metadata record

DC FieldValue Language
dc.contributor.authorTillu, Diptien
dc.contributor.authorMelemedjian, Ohannesen
dc.contributor.authorAsiedu, Marinaen
dc.contributor.authorQu, Ningen
dc.contributor.authorDe Felice, Milenaen
dc.contributor.authorDussor, Gregoryen
dc.contributor.authorPrice, Theodoreen
dc.date.accessioned2016-05-20T09:01:19Z-
dc.date.available2016-05-20T09:01:19Z-
dc.date.issued2012en
dc.identifier.citationTillu et al. Molecular Pain 2012, 8:5 http://www.molecularpain.com/content/8/1/5en
dc.identifier.doi10.1186/1744-8069-8-5en
dc.identifier.urihttp://hdl.handle.net/10150/610215-
dc.description.abstractBACKGROUND:Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.RESULTS:To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.CONCLUSIONS:These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://mpx.sagepub.com/content/8/1744-8069-8-5.fullen
dc.rights© 2012 Tillu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.titleResveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic painen
dc.typeArticleen
dc.identifier.eissn1744-8069en
dc.contributor.departmentDepartment of Pharmacology, University of Arizona, 1501 N Campbell Ave, PO BOX 245050, Tucson, AZ 85724, USAen
dc.contributor.departmentGraduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, USAen
dc.contributor.departmentBio5 Institute, University of Arizona, Tucson, USAen
dc.identifier.journalMolecular Painen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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