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

Persistent Link:
http://hdl.handle.net/10150/578927
Title:
Angiotensin-(1-7) as an Antinociceptive Agent in Cancer-Induced Bone Pain
Author:
Forte, Brittany Leigh
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Many cancerous solid tumors, such as breast, metastasize to the bone and induce bone pain (CIBP). CIBP is often severe due to an enhanced inflammation in the bone microenvironment, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain but may enhance bone loss and induce analgesic tolerance, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)), a product of Angiotensin II cleavage by Angiotensin-Converting Enzyme 2, binds and activates the Mas receptor, a G(q/11)-protein coupled receptor (MasR). Angiotensin-(1-7)/MasR activation modulates the inflammatory signaling after acute tissue insult resulting in altered production of reactive oxygen species and further inflammatory response, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. Therefore, we hypothesized that Ang-(1-7), acting at the MasR, inhibits CIBP by reducing proinflammatory cytokines/chemokines in an immunocompetent murine model of breast cancer-induced bone pain. Murine breast cancer cells, 66.1, were implanted into the femur of mice and allowed to establish and proliferate for 7 days. Cancer inoculation increased spontaneous and evoked pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after chronic administration (p<0.01); co-administration of a MasR antagonist reversed this reduction. Cytokine/chemokine profiling of bone marrow extrudates from Ang-(1-7) mice of the cancer studies revealed significant increases in the relative expression of C5/C5a, IL-1ra, IL-16, M-CSF, MIG, with concomitant decreases in the expression of MIP-1α compared to vehicle controls (p<0.05). Ang-(1-7) administration normalized levels of IL-1ra and MIP-1α in the bone-tumor micro-environment. Data here suggest that modifying the cancer-induced inflammatory response in the bone-tumor micro-environment with Ang-(1-7) through the Mas receptor significantly attenuates CIBP, which may be an alternative therapeutic strategy for the nearly 70% of advanced stage cancer patients who experience excruciating pain.
Type:
text; Electronic Thesis
Degree Name:
B.S.
Degree Level:
bachelors
Degree Program:
Honors College; Biochemistry
Degree Grantor:
University of Arizona
Advisor:
Vanderah, Todd W.; Montfort, William R.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleAngiotensin-(1-7) as an Antinociceptive Agent in Cancer-Induced Bone Painen_US
dc.creatorForte, Brittany Leighen
dc.contributor.authorForte, Brittany Leighen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractMany cancerous solid tumors, such as breast, metastasize to the bone and induce bone pain (CIBP). CIBP is often severe due to an enhanced inflammation in the bone microenvironment, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain but may enhance bone loss and induce analgesic tolerance, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)), a product of Angiotensin II cleavage by Angiotensin-Converting Enzyme 2, binds and activates the Mas receptor, a G(q/11)-protein coupled receptor (MasR). Angiotensin-(1-7)/MasR activation modulates the inflammatory signaling after acute tissue insult resulting in altered production of reactive oxygen species and further inflammatory response, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. Therefore, we hypothesized that Ang-(1-7), acting at the MasR, inhibits CIBP by reducing proinflammatory cytokines/chemokines in an immunocompetent murine model of breast cancer-induced bone pain. Murine breast cancer cells, 66.1, were implanted into the femur of mice and allowed to establish and proliferate for 7 days. Cancer inoculation increased spontaneous and evoked pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after chronic administration (p<0.01); co-administration of a MasR antagonist reversed this reduction. Cytokine/chemokine profiling of bone marrow extrudates from Ang-(1-7) mice of the cancer studies revealed significant increases in the relative expression of C5/C5a, IL-1ra, IL-16, M-CSF, MIG, with concomitant decreases in the expression of MIP-1α compared to vehicle controls (p<0.05). Ang-(1-7) administration normalized levels of IL-1ra and MIP-1α in the bone-tumor micro-environment. Data here suggest that modifying the cancer-induced inflammatory response in the bone-tumor micro-environment with Ang-(1-7) through the Mas receptor significantly attenuates CIBP, which may be an alternative therapeutic strategy for the nearly 70% of advanced stage cancer patients who experience excruciating pain.en
dc.typetexten
dc.typeElectronic Thesisen
thesis.degree.nameB.S.en
thesis.degree.levelbachelorsen
thesis.degree.disciplineHonors Collegeen
thesis.degree.disciplineBiochemistryen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorVanderah, Todd W.en
dc.contributor.advisorMontfort, William R.en
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