Programmed Cell Death Protein 1 Contributes to Oral Cancer Pain via Regulating Tumor Necrosis Factor Alpha in the Spinal Trigeminal Nucleus Caudalis

Runyi Mao; Sufang Liu; John C Dolan; Brian L Schmidt; Feng Tao

doi:10.2174/1570159X23666241209160039

Programmed Cell Death Protein 1 Contributes to Oral Cancer Pain via Regulating Tumor Necrosis Factor Alpha in the Spinal Trigeminal Nucleus Caudalis

Curr Neuropharmacol. 2024 Dec 9. doi: 10.2174/1570159X23666241209160039. Online ahead of print.

Authors

Runyi Mao¹, Sufang Liu¹, John C Dolan², Brian L Schmidt^{2

3}, Feng Tao¹

Affiliations

¹ Department of Biomedical Sciences, Texas A&M University School of Dentistry, Dallas, Texas, USA.
² NYU Dentistry Translational Research Center, New York University College of Dentistry, New York, NY, USA.
³ Pain Research Center, New York University, New York, NY, USA.

PMID: 39660489
DOI: 10.2174/1570159X23666241209160039

Abstract

Background: Oral cancer causes intense pain at the primary site, and such pain can impair oral functions. However, the underlying mechanisms for oral cancer pain are still not fully understood. In the present study, it is investigated whether programmed cell death protein 1 (PD-1) is involved in the development of oral cancer pain.

Methods: RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C) and measured pain behaviors using von Frey filaments and dolognawmeter. Western blotting and immunofluorescence staining were performed to analyze the expression of PD-1 and tumor necrosis factor alpha (TNFα) in the Sp5C.

Results: It was observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in our oral cancer pain mouse model. Moreover, we found that TNFα was highly upregulated in the Sp5C following the induction of oral cancer pain and that intra-Sp5C injection of the PD-1 antibody diminished the upregulation of TNFα. It was found that genetic deletion of TNFα or its receptor antagonism synergized the analgesic effect of PD-1 antibody on oral cancer pain.

Conclusion: Our results suggest that PD-1 in the Sp5C contributes to oral cancer pain by altering TNFα signaling in the trigeminal nociceptive system, and PD-1 could be targeted to develop a novel approach for oral cancer pain management.

Keywords: Oral cancer pain; functional allodynia; hypersensitivity; programmed cell death protein 1; spinal trigeminal nucleus caudalis; tumor necrosis factor-alpha..