Tally M Largent-Milnes

Tally M Largent-Milnes

Assistant Professor, Pharmacology
Assistant Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(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

Deekonda, S., Wugalter, L., Rankin, D., Largent-Milnes, T. M., Davis, P., Wang, Y., Bassirirad, N. M., Lai, J., Kulkarni, V., Vanderah, T. W., Porreca, F., & Hruby, V. J. (2015). Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives. Bioorganic & medicinal chemistry letters, 25(20), 4683-8.

We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.

Tumati, S., Largent-Milnes, T. M., Keresztes, A., Ren, J., Roeske, W. R., Vanderah, T. W., & Varga, E. V. (2012). Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist. Journal of neuroimmunology, 244(1-2), 23-31.

Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine-mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1β, TNFα) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment.

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 (10 Hz) at 35°C. Of all recorded neurons, those with High basal release rates (67%) at near-physiological temperatures greatly reduced their sEPSC rate when cooled to 30°C without amplitude changes. Such responses persisted during blockade of action potentials indicating that the High rate of glutamate release arises from presynaptic thermal mechanisms. Neurons with Low basal frequencies (33%) showed minor thermal changes in sEPSC rate that were abolished after addition of TTX, suggesting these responses were indirect and required local circuits. Activation of TRPV1 with capsaicin (100 nM) increased miniature EPSC (mEPSC) frequency in 70% of neurons, but half of these neurons had Low basal mEPSC rates and no temperature sensitivity. Our evidence indicates that normal temperatures (35-37°C) drive spontaneous excitatory synaptic activity within superficial Vc by a mechanism independent of presynaptic action potentials. Thus thermally sensitive inputs on superficial Vc neurons may tonically activate these neurons without afferent stimulation.

Tumati, S., Roeske, W. R., Largent-Milnes, T. M., Vanderah, T. W., & Varga, E. V. (2011). Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats. Journal of neuroscience methods, 199(1), 62-8.

Sustained morphine treatment has been shown to produce paradoxical pain sensitization (opioid-induced hyperalgesia) and also causes increase in spinal pain neurotransmitter, such as calcitonin gene related peptide (CGRP), concentration in experimental animals. Studies have also shown that cyclic adenosine-monophosphate (cAMP)-dependent protein kinase (PKA) plays a major role in the regulation of presynaptic neurotransmitter (such as CGRP and substance P) synthesis and release. We have previously shown that in cultured primary sensory dorsal root ganglion (DRG) neurons sustained in vitro opioid agonist treatment upregulates cAMP levels (adenylyl cyclase (AC) superactivation) and augments basal and capsaicin evoked CGRP release in a PKA dependent manner. In the present study, we investigated the in vivo role of PKA in sustained morphine-mediated pain sensitization. Our data indicate that selective knock-down of spinal PKA activity by intrathecal (i.th.) pretreatment of rats with a PKA-selective small interference RNA (siRNA) mixture significantly attenuates sustained morphine-mediated augmentation of spinal CGRP immunoreactivity, thermal hyperalgesia, mechanical allodynia and antinociceptive tolerance. The present findings indicate that sustained morphine-mediated activation of spinal cAMP/PKA-dependent signaling may play an important role in opioid induced hyperalgesia.