title: Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain.
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.
authors.affiliation: Department of Pharmacology, University of Arizona, 1501 N Campbell Ave, PO BOX 245050, Tucson, AZ 85724, USA.
authors.forename: Dipti V
authors.initials: DV
authors.lastname: Tillu
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.forename: Ning
authors.initials: N
authors.lastname: Qu
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D059787:Acute Pain / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006930:Hyperalgesia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010149:Postoperative Pain / Q000150:complications / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D000077185:Resveratrol; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D039562:Eukaryotic Initiation Factor-4F; D015850:Interleukin-6; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol