A Novel Syngeneic Immunocompetent Mouse Model of Head and Neck Cancer Pain Independent of Interleukin-1 Signaling

Anesth Analg. 2021 Apr 1;132(4):1156-1163. doi: 10.1213/ANE.0000000000005302.


Background: Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling.

Methods: Male C57BL/6 mice were injected with a murine model of human papillomavirus (HPV+)-induced oropharyngeal squamous cell carcinoma in their right hindlimb to induce tumor growth. Pain sensitivity was measured via von Frey filaments. Spontaneous pain was assessed via the facial grimace scale. IL-1β was measured by quantifying gene expression via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA).

Results: Pain hypersensitivity and spontaneous pain develop quickly after the implantation of tumor cells, a time when tumor volume is still insignificant. Spinal and circulating IL-1β levels are significantly elevated in tumor-bearing mice. Blocking IL-1 signaling either by intrathecal administration of interleukin-1 receptor antagonist (IL-1ra) or by genetic deletion (interleukin-1 receptor knockout [Il1r1-/-]) does not alleviate HNCP.

Conclusions: We established the first syngeneic model of HNCP in immunocompetent mice. Unlike inflammatory or nerve-injured pain, HNCP is independent of IL-1 signaling. These findings challenge the common belief that pain results from tissue compression or IL-1 signaling in patients with head and neck cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cancer Pain / etiology*
  • Cancer Pain / metabolism
  • Cancer Pain / physiopathology
  • Cell Line, Tumor
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin-1beta / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oropharyngeal Neoplasms / complications*
  • Oropharyngeal Neoplasms / metabolism
  • Oropharyngeal Neoplasms / virology
  • Pain Threshold
  • Papillomaviridae / pathogenicity
  • Signal Transduction
  • Spinal Cord / metabolism*
  • Spinal Cord / physiopathology
  • Squamous Cell Carcinoma of Head and Neck / complications*
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Squamous Cell Carcinoma of Head and Neck / virology


  • IL1B protein, mouse
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta