Inhibition of TNF reduces mechanical orofacial hyperalgesia induced by Complete Freund's Adjuvant by a TRPV1-dependent mechanism in mice

Pharmacol Rep. 2017 Dec;69(6):1380-1385. doi: 10.1016/j.pharep.2017.05.013. Epub 2017 Jun 3.


Background: Inflammation in the orofacial region results in pain and is associated with many pathological states, including migraine, neuralgias and temporomandibular disorder. Although extensively studied, the mechanisms responsible for these conditions are not known and effective treatments are lacking. We reported earlier that the proinflammatory cytokine tumor necrosis factor (TNF) plays an important role in regulation of trigeminal ganglion (TG) neuron function in vitro. In the present study we investigated the role of TNF in mechanical hypersensitivity in mice.

Methods: We employed the Complete Freund's Adjuvant (CFA)-induced model of orofacial pain and evaluated the effect of blocking of soluble TNF activity by peripheral administration of the novel dominant negative TNF biologic, XPro1595.

Results: We show that CFA administration into the lower lip causes hyperalgesia and an increase in both expression of transient receptor potential vanilloid subfamily member 1 (TRPV1) mRNA and in the average intensity of TRPV1 protein immunoreactivity in TG neurons. We also show that intraperitoneal administration of XPro1595 prevents both CFA-induced mechanical hypersensitivity and, as shown in immunohistochemical staining - upregulation of TRPV1 protein expression in TG neurons.

Conclusions: We conclude that one of the possible regulatory mechanisms of TNF in pain involves upregulation of the nociceptor TRPV1, and that peripheral treatment with a selective anti-soluble TNF biologic can prevent hyperalgesia caused by inflammation in the orofacial region. Therefore, these new findings suggest that XPro1595 may serve as a novel treatment for orofacial pain disorders.

Keywords: CFA; Orofacial pain; TNF; TRPV1; Trigeminal.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Facial Pain / physiopathology*
  • Facial Pain / prevention & control
  • Freund's Adjuvant / administration & dosage
  • Hyperalgesia / physiopathology*
  • Hyperalgesia / prevention & control
  • Inflammation / drug therapy
  • Inflammation / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / metabolism
  • Trigeminal Ganglion / metabolism
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • XENP 1595
  • Freund's Adjuvant