Angiotensin‐(1‐7) as an Antinociceptive Agent in Cancer‐Induced Bone Pain

Abstract

Many cancerous solid tumors, including breast, metastasize to the bone and induce pain (CIBP). CIBP is often severe due to an enhanced inflammation in the bone, rapid bone degradation, and nociceptor sprouting. Opioids are often prescribed to manage this pain but may lead to enhanced bone loss and analgesic tolerance, compromising patient quality of life. Angiotensin‐(1‐7) (Ang1‐7), a product of Angiotensin II degradation, binds and activates the Mas receptor, a Gq/11‐protein coupled receptor (MasR). MasR activation after acute tissue insult results in diminished production of reactive species and further inflammatory response, yet no studies have investigated whether Ang1‐7/MasR play a role in CIBP. Therefore, we hypothesized Ang1‐7 acts via the MasR to inhibit CIBP by reducing proinflammatory cytokines and slowing bone loss in a murine model of breast CIBP. Cancer inoculation of the femur increased spontaneous and evoked pain behaviors that were significantly reduced after Ang1‐7 administration (p<0.01); co‐administration of a MasR antagonist reversed this reduction. Cytokine/chemokine profiles of femur extrudates from Ang1‐7 mice revealed significant increases in the relative expression of C5/C5a, IL‐1ra, IL‐16, M‐CSF, MIG, and decrease in the expression of MIP‐1α compared to vehicle controls (p<0.05). Although Ang1‐7 intervention changed the composition of inflammatory mediators in the bone‐tumor microenvironment, bone degradation was not impacted. Nearly 70% of advanced stage cancer patients experience excruciating pain that may be exacerbated by available analgesics, while data here suggests modifying the cancer‐induced inflammatory response in the bone microenvironment with Ang1‐7 via MasR significantly attenuates CIBP. Studies funded by the Department of Pharmacology at the University of Arizona.