title: Hypoxia-inducible factor 1 regulates heat and cold pain sensitivity and persistence.
abstract: OBJECTIVE
  The present study assessed the functions of the transcription factor hypoxia-inducible factor (HIF) in sensory neurons in models of acute, inflammatory, ischemic, and neuropathic pain. The alpha subunit, HIF1α, was specifically deleted in neurons of the dorsal root ganglia by mating HIF1α(fl/fl) mice with SNScre mice.
  
  
  RESULTS
  SNS-HIF1α(-/-) mice were more sensitive to noxious heat and cold pain stimulation than were HIF1α(fl/fl) control mice. They also showed heightened first-phase nociceptive responses in the formalin and capsaicin tests with increased numbers of cFos-positive neurons in the dorsal horn, and intensified hyperalgesia in early phases after paw inflammation and hind limb ischemia/reperfusion. The behavioral cold and heat pain hypersensitivity was explained by increased calcium fluxes after transient receptor potential channel activation in primary sensory neurons of SNS-HIF1α(-/-) mice and lowered electrical activation thresholds of sensory fibers. SNS-HIF1α(-/-) mice however, developed less neuropathic pain after sciatic nerve injury, which was associated with an abrogation of HIF1-mediated gene up-regulation.
  
  
  METHODS
  The results suggest that HIF1α is protective in terms of acute heat and cold pain but in case of ongoing activation in injured neurons, it may promote the development of neuropathic pain.
  
  
  CONCLUSIONS
  The duality of HIF1 in pain regulation may have an impact on the side effects of drugs targeting HIF1, which are being developed, for example, as anticancer agents. Specifically, in patients with cancer neuropathy, however, temporary HIF1 inhibition might provide a welcome combination of growth and pain reduction.
authors.affiliation: 1 Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt , Frankfurt, Germany .
authors.forename: Maike
authors.initials: M
authors.lastname: Kanngiesser
authors.forename: Norbert
authors.initials: N
authors.lastname: Mair
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Lim
authors.forename: Katja
authors.initials: K
authors.lastname: Zschiebsch
authors.forename: Johanna
authors.initials: J
authors.lastname: Blees
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiròs
authors.forename: Michaela
authors.initials: M
authors.lastname: Kress
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D003080:Cold Temperature; D005260:Female; D006358:Hot Temperature; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017288:Pain Threshold
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit