1. OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients
- Author
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Viet, Chi T, Dang, Dongmin, Aouizerat, Bradley E, Miaskowski, Christine, Ye, Yi, Viet, Dan T, Ono, Kentaro, and Schmidt, Brian L
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Cancer ,Genetics ,Pain Research ,Chronic Pain ,Drug Abuse (NIDA only) ,Substance Misuse ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Aged ,Analgesics ,Opioid ,Animals ,Cancer Pain ,Cell Line ,Tumor ,Cohort Studies ,DNA Methylation ,Drug Tolerance ,Epigenesis ,Genetic ,Female ,Humans ,Male ,Mice ,Inbred BALB C ,Middle Aged ,Morphine ,Neoplasm Transplantation ,Neoplasms ,Nociceptive Pain ,Opioid-Related Disorders ,Pain Management ,Patient Education as Topic ,Pharmacogenomic Testing ,Receptors ,Opioid ,mu ,Methylation ,cancer pain ,mu-opioid receptor ,OPRM1 ,opioid tolerance ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Anesthesiology ,Clinical sciences ,Epidemiology - 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.PerspectiveWe 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.
- Published
- 2017