OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Chi T. Viet, Dongmin Dang, Bradley E. Aouizerat, Christine Miaskowski, Yi Ye, Dan T. Viet, Kentaro Ono, Brian L. Schmidt

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons. Perspective We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model.

Original languageEnglish (US)
Pages (from-to)1046-1059
Number of pages14
JournalJournal of Pain
Volume18
Issue number9
DOIs
StatePublished - Sep 2017

Keywords

  • Methylation
  • OPRM1
  • cancer pain
  • mu-opioid receptor
  • opioid tolerance

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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