Tally M Largent-Milnes
Assistant Professor, BIO5 Institute
Assistant Professor, Pharmacology
Primary Department
Department Affiliations
(520) 626-6400
Research Interest
Dr. Tally Largent-Milnes Ph.D., is a Research Assistant Professor of Pharmacology at the University of Arizona. Dr. Largent-Milnes is a member of the International Association for the Study of Pain, the Society for Neuroscience, and the American Pain Society. Her major research focus is on trigeminal (Vc) synaptic physiology, neuropathic pain and rational design of multifunctional compounds to treat chronic pain. Dr. Largent-Milnes uses whole-cell patch clamp electrophysiology, immunohistochemistry, behavior, and pharmacology, to explore excitatory synaptic transmission between trigeminal afferents and nucleus caudalis (Vc) neurons as well as the adaptations that accompany certain pathologies/pharmacological interventions. Her work is critical to improve our understanding of the construction of the trigeminal system at the synaptic level, and will allow for the development of better therapeutics to treat select craniofacial pain disorders through her research.

Publications

Francois-Moutal, L., Wang, Y., Moutal, A., Cottier, K. E., Melemedjian, O. K., Yang, X., Wang, Y., Ju, W., Largent-Milnes, T. M., Khanna, M., Vanderah, T. W., & Khanna, R. (2015). A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. PAIN, 156(7), 1247-1264.
BIO5 Collaborators
Rajesh Khanna, Tally M Largent-Milnes
Moutal, A., Dustrude, E. T., Largent-Milnes, T. M., Vanderah, T. W., Khanna, M., & Khanna, R. (2017). Blocking CRMP2 SUMOylation reverses neuropathic pain. Molecular psychiatry.
BIO5 Collaborators
Rajesh Khanna, Tally M Largent-Milnes
Forte, B. L., Slosky, L. M., Zhang, H., Arnold, M. R., Staatz, W. D., Hay, M., Largent-Milnes, T. M., & Vanderah, T. W. (2016). Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain. Pain, 157(12), 2709-2721.
BIO5 Collaborators
Meredith Hay, Tally M Largent-Milnes

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.

Lozano-Ondoua, A. N., Wright, C., Vardanyan, A., King, T., Largent-Milnes, T. M., Nelson, M., Jimenez-Andrade, J. M., Mantyh, P. W., & Vanderah, T. W. (2010). A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. Life sciences, 86(17-18), 646-53.

Cannabinoid CB(2) agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB(2) agonist, does not demonstrate central nervous system side effects seen with CB(1) agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB(2) selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB(2) agonist administered over a 7day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation.

Largent-Milnes, T. M., Hegarty, D. M., Aicher, S. A., & Andresen, M. C. (2014). Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons. Journal of neurophysiology, 111(11), 2222-31.

Trigeminal sensory afferent fibers terminating in nucleus caudalis (Vc) relay sensory information from craniofacial regions to the brain and are known to express transient receptor potential (TRP) ion channels. TRP channels are activated by H(+), thermal, and chemical stimuli. The present study investigated the relationships among the spontaneous release of glutamate, temperature, and TRPV1 localization at synapses in the Vc. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from Vc neurons (n = 151) in horizontal brain-stem slices obtained from Sprague-Dawley rats. Neurons had basal sEPSC rates that fell into two distinct frequency categories: High (≥10 Hz) or Low (