A Kappa Opioid Receptor Agonist Blocks Bone Cancer Pain Without Altering Bone Loss, Tumor Size, or Cancer Cell Proliferation in a Mouse Model of Cancer-Induced Bone Pain.

TitleA Kappa Opioid Receptor Agonist Blocks Bone Cancer Pain Without Altering Bone Loss, Tumor Size, or Cancer Cell Proliferation in a Mouse Model of Cancer-Induced Bone Pain.
Publication TypeJournal Article
Year of Publication2018
AuthorsEdwards KA, Havelin JJ, McIntosh MI, Ciccone HA, Pangilinan K, Imbert I, Largent-Milnes TM, King T, Vanderah TW, Streicher JM
JournalJ Pain
Volume19
Issue6
Pagination612-625
Date Published2018 06
ISSN1528-8447
Keywords3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Analgesics, Non-Narcotic, Animals, Bone and Bones, Cancer Pain, Cell Proliferation, Disease Models, Animal, Female, Mice, Receptors, Opioid, kappa
Abstract

Breast cancer metastasizes to bone, diminishing quality of life of patients because of pain, fracture, and limited mobility. Cancer-induced bone pain (CIBP) is characterized as moderate to severe ongoing pain, primarily managed by mu opioid agonists such as fentanyl. However, opioids are limited by escalating doses and serious side effects. One alternative may be kappa opioid receptor (KOR) agonists. There are few studies examining KOR efficacy on CIBP, whereas KOR agonists are efficacious in peripheral and inflammatory pain. We thus examined the effects of the KOR agonist U50,488 given twice daily across 7 days to block CIBP, tumor-induced bone loss, and tumor burden. U50,488 dose-dependently blocked tumor-induced spontaneous flinching and impaired limb use, without changing tactile hypersensitivity, and was fully reversed by the KOR antagonist nor-binaltorphimine. U50,488 treatment was higher in efficacy and duration of action at later time points. U50,488 blocked this pain without altering tumor-induced bone loss or tumor growth. Follow-up studies in human cancer cell lines confirmed that KOR agonists do not affect cancer cell proliferation. These studies suggest that KOR agonists could be a new target for cancer pain management that does not induce cancer cell proliferation or alter bone loss.

PERSPECTIVE: This study demonstrates the efficacy of KOR agonists in the treatment of bone cancer-induced pain in mice, without changing tumor size or proliferation in cancer cell lines. This suggests that KOR agonists could be used to manage cancer pain without the drawbacks of mu opioid agonists and without worsening disease progression.

DOI10.1016/j.jpain.2018.01.002
Alternate JournalJ Pain
PubMed ID29371114
Grant ListP20 GM103643 / GM / NIGMS NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD
John M. Streicher, PhD
Todd Vanderah, PhD