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.


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.

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
Sandweiss, A. J., Azim, A., Ibraheem, K., Largent-Milnes, T. M., Rhee, P., Vanderah, T. W., & Joseph, B. (2017). Remote ischemic conditioning preserves cognition and motor coordination in a mouse model of traumatic brain injury. The journal of trauma and acute care surgery, 83(6), 1074-1081.

Management of traumatic brain injury (TBI) is focused on minimizing or preventing secondary brain injury. Remote ischemic conditioning (RIC) is an established treatment modality that has been shown to improve patient outcomes in different clinical settings by influencing inflammatory insults. In a clinical trial, RIC showed amelioration of SB100 and neuron-specific enolase. The aim of our study was to further elucidate the mechanisms and outcome when applying RIC in a mouse model of traumatic brain injury.

Ibrahim, M. M., Patwardhan, A., Gilbraith, K. B., Moutal, A., Yang, X., Chew, L. A., Largent-Milnes, T., Malan, T. P., Vanderah, T. W., Porreca, F., & Khanna, R. (2017). Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain, 158(2), 347-360.

Treatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain. We investigated the effects of light-emitting diodes (LEDs), in the visible spectrum, on acute sensory thresholds in naive rats as well as in experimental neuropathic pain. Rats receiving green LED light (wavelength 525 nm, 8 h/d) showed significantly increased paw withdrawal latency to a noxious thermal stimulus; this antinociceptive effect persisted for 4 days after termination of last exposure without development of tolerance. No apparent side effects were noted and motor performance was not impaired. Despite LED exposure, opaque contact lenses prevented antinociception. Rats fitted with green contact lenses exposed to room light exhibited antinociception arguing for a role of the visual system. Antinociception was not due to stress/anxiety but likely due to increased enkephalins expression in the spinal cord. Naloxone reversed the antinociception, suggesting involvement of central opioid circuits. Rostral ventromedial medulla inactivation prevented expression of light-induced antinociception suggesting engagement of descending inhibition. Green LED exposure also reversed thermal and mechanical hyperalgesia in rats with spinal nerve ligation. Pharmacological and proteomic profiling of dorsal root ganglion neurons from green LED-exposed rats identified changes in calcium channel activity, including a decrease in the N-type (CaV2.2) channel, a primary analgesic target. Thus, green LED therapy may represent a novel, nonpharmacological approach for managing pain.