Calcitonin Related Polypeptide Alpha Mediates Oral Cancer Pain

Nguyen Huu Tu, Kenji Inoue, Parker K. Lewis, Ammar Khan, Jun Hyeong Hwang, Varun Chokshi, Branka Brukner Dabovic, Shanmugapriya Selvaraj, Aditi Bhattacharya, Zinaida Dubeykovskaya, Nathalie M. Pinkerton, Nigel W. Bunnett, Cynthia A. Loomis, Donna G. Albertson, Brian L. Schmidt

Research output: Contribution to journalArticlepeer-review


Oral cancer patients suffer pain at the site of the cancer. Calcitonin gene related polypeptide (CGRP), a neuropeptide expressed by a subset of primary afferent neurons, promotes oral cancer growth. CGRP also mediates trigeminal pain (migraine) and neurogenic inflammation. The contribution of CGRP to oral cancer pain is investigated in the present study. The findings demonstrate that CGRP-immunoreactive (-ir) neurons and neurites innervate orthotopic oral cancer xenograft tumors in mice. Cancer increases anterograde transport of CGRP in axons innervating the tumor, supporting neurogenic secretion as the source of CGRP in the oral cancer microenvironment. CGRP antagonism reverses oral cancer nociception in preclinical oral cancer pain models. Single-cell RNA-sequencing is used to identify cell types in the cancer microenvironment expressing the CGRP receptor components, receptor activity modifying protein 1 Ramp1 and calcitonin receptor like receptor (CLR, encoded by Calcrl). Ramp1 and Calcrl transcripts are detected in cells expressing marker genes for Schwann cells, endothelial cells, fibroblasts and immune cells. Ramp1 and Calcrl transcripts are more frequently detected in cells expressing fibroblast and immune cell markers. This work identifies CGRP as mediator of oral cancer pain and suggests the antagonism of CGRP to alleviate oral cancer pain.

Original languageEnglish (US)
Article number1675
Issue number13
StatePublished - Jul 2023


  • CGRP
  • cancer innervation
  • oral cancer
  • pain
  • peptidergic neurons

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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