title: Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain.
abstract: Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain.
authors.affiliation: aDepartment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA bDepartment of Physiology, Evelyn McKnight Brain Institute, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Forte
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Slosky
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Moriah R
authors.initials: MR
authors.lastname: Arnold
authors.forename: William D
authors.initials: WD
authors.lastname: Staatz
authors.forename: Meredith
authors.initials: M
authors.lastname: Hay
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000803:Angiotensin I / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D057912:Angiotensin II Type 2 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D000072716:Cancer Pain / Q000188:drug therapy* / Q000209:etiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009425:Nesting Behavior / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use; D045442:Rotarod Performance Test
chemical_list: D000700:Analgesics; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; C073402:PD 123319; D000803:Angiotensin I; C118790:angiotensin I (1-7); D019808:Losartan