title: Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity.
abstract: BACKGROUND
  Tumor necrosis factor alpha (TNFα) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFα dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFα dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild-type (WT) and TNFR1/2 KO mice.
  
  
  METHODS
  Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10weeks post.
  
  
  RESULTS
  TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10-week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in WT mice. Proteomic profiling 10weeks after chronic TIC injury revealed TNFα, interleukin-1alpha (IL-1α), interleukin-5 (IL-5), interleukin-23 (IL-23), macrophage inflammatory protein-1β (MIP-1β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased more than 2-fold in TNFR1/2 KO mice compared to WT mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 mitogen-activated protein kinase (MAPK) inhibitor and microglial inhibitor minocycline reduced hypersensitivity.
  
  
  CONCLUSIONS
  The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFα dysregulation. Data support involvement of both neurogenic and humoral influences in chronic neuropathic pain.
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: fei.ma@uky.edu.
authors.forename: F
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: lzhanh@email.uky.edu.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: hoz2@email.uky.edu.
authors.forename: H S
authors.initials: HS
authors.lastname: Oz
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: mark.mashni3@uky.edu.
authors.forename: M
authors.initials: M
authors.lastname: Mashni
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: kwhigh2@uky.edu.
authors.forename: K N
authors.initials: KN
authors.lastname: Westlund
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005157:Facial Pain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020543:Proteome / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D014110:Touch; D061221:Trigeminal Nerve Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020543:Proteome; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: MAPK; mechanical allodynia; microglia; minocycline; neuropathic pain; trigeminal inflammatory compression