Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma

Pain. 2023 Jan 1;164(1):27-42. doi: 10.1097/j.pain.0000000000002655. Epub 2022 Apr 20.


Head and neck squamous cell carcinoma (HNSCC) causes more severe pain and psychological stress than other types of cancer. Despite clinical evidence linking pain, stress, and cancer progression, the underlying relationship between pain and sympathetic neurotransmission in oral cancer is unknown. We found that human HNSCC tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. Moreover, β-adrenergic 1 and 2 receptors (β-ARs) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased β-AR2 protein expression as well as cancer cell proliferation in vitro. We have recently demonstrated that inhibition of tumor necrosis factor alpha (TNFα) signaling reduces oral cancer-induced nociceptive behavior. Norepinephrine-treated cancer cell lines secrete more TNFα which, when applied to tongue-innervating trigeminal neurons, evoked a larger Ca 2+ transient; TNF-TNFR inhibitor blocked the increase in the evoked Ca 2+ transient. Using an orthotopic xenograft oral cancer model, we found that mice demonstrated significantly less orofacial cancer-induced nociceptive behavior during systemic β-adrenergic inhibitory treatment with propranolol. Furthermore, chemical sympathectomy using guanethidine led to a significant reduction in tumor size and nociceptive behavior. We infer from these results that sympathetic signaling modulates oral cancer pain through TNFα secretion and tumorigenesis. Further investigation of the role of neurocancer communication in cancer progression and pain is warranted.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Agents / therapeutic use
  • Animals
  • Carcinoma, Squamous Cell* / complications
  • Carcinoma, Squamous Cell* / drug therapy
  • Cell Line, Tumor
  • Head and Neck Neoplasms*
  • Humans
  • Mice
  • Mouth Neoplasms* / complications
  • Nociception
  • Norepinephrine / pharmacology
  • Norepinephrine / therapeutic use
  • Pain
  • Squamous Cell Carcinoma of Head and Neck
  • Tumor Necrosis Factor-alpha / metabolism


  • Tumor Necrosis Factor-alpha
  • Norepinephrine
  • Adrenergic Agents