Todd W. Vanderah
Associate Professor of Pharmacology and Anesthesiology
Ph.D., University of Arizona, 1995
Life Sciences North 560
(520) 626-7801
vanderah@u.arizona.edu
Research Interests
- Mechanisms of neuropathic pain
- Neuronal integration in pain pathways
- Neurochemical release during conditions of neuropathy
- Neuronal plasticity
- Opioid receptor pharmacology
- Novel targets for drug discovery
Technical Expertise: Cellular and Molecular Neuropharmacology
- Behavioral drug administration
- Behavioral testing
- Rodent surgeries
- CNS microdialysis
- Neurotransmitter release using superfusion
- Analytical measurements including RIA and HPLC
- Antisense strategies in vivo
Highlight of Our Research
Cholecystokinin and receptors as therapeutic targets
Recently we have demonstrated both behaviorally and by using microdialysis that the neuropeptide, cholecystokinin (CCK), promotes neuropathic pain by activating descending projection neurons that originate in a region of the brainstem known as the rostral ventromedial medulla (RVM). An increase in the level of release of CCK in the RVM is evident after nerve injury as well as after repeated administration of morphine. This enhanced activity of CCK mediated activation of RVM neurons maintains neuropathic pain, and is also important in the development of analgesic tolerance to spinal morphine after chronic morphine treatment. Thus, CCK antagonism may potentiate morphine antinociception under conditions of neuropathy or chronic morphine. Our collaboration with Dr. Victor Hruby in the Department of Chemistry aims to identify novel molecules that have bifunctional opioid agonist and CCK antagonist actions as prototypes for analgesics for chronic, neuropathic pain.
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Sensory neuron function and GPCR
Sensory nerves that propagate painful signals are highly specialized nerves called nociceptors. The activation of these nociceptors includes noxious stimuli like heat, cold, pressure and chemicals. The excitability of these nociceptors is modulated by a number of G-protein coupled receptors (GPCR) both at their central termini in the spinal cord and in their peripheral nerve endings, which contain one or more specialized cation channels that are activated by specific noxious input. We are interested in how GPCR modulate the activity of these specialized cation channels, in particular the vanilloid receptors that mediate noxious heat, to regulate sensory thresholds in acute and chronic pain conditions.
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Selected Publications
Vanderah, T.W., Gardell, L.R., Burgess, S.E., Ibrahim, J., Zhong, C-M., Ossipov, M.H., Lai, J., Malan, Jr. T.P. and Porreca, F.: Repeated Spinal Opioid Administration Produces Abnormal Pain and Antinociceptive Tolerance which is Reversed by Dynorphin Antiserum. J Neurosci., 20(18): 7074-7079, 2000.
Vanderah, T.W., Suenaga N.M.H., Ossipov, M.H., Malan Jr., T.P., Lai, J. and Porreca, F. Tonic Descending Facilitation From The Rostral Ventromedial Medulla Mediates Opioid-Induced Abnormal Pain and Antinociceptive Tolerance. J. Neurosci., 21(1): 279-286, 2001.
Rasband, S.N., Park, E.W., Vanderah, T.W., Lai, J., Porreca, F. and Trimmer, J.S. Distinct Potassium Channels on Pain-Sensing Neurons. PNAS, 98(23): 13373-78, 2001.
Wessells, H., Hruby V.J., Hackett, J., Han, G., Balse-Srinivasan, P. and Vanderah, T.W.: MT-II Induces Penile Erection via Brain and Spinal Melanocortin Receptors. Neuroscience, 118: 755-762, 2003.
Ibrahim, M.M., Deng, H., Zvonok, A., Cockayne, D.A., Kwan, J., Mata, H.P., Vanderah, T.W., Lai, J., Porreca, F., Makriyannis, A. and Malan Jr.T.P.: Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS. PNAS, 100(18): 10529-10533, 2003
Gardell, L.R., Ehrenfels, C., Ossipov, M.H., Rossomando, AJ., Miller, S., Cai, C., Walus, L., Carmillo, P., Tse, A., Worley, D., Pepinsky, B., Cate, R., Vanderah, T.W., Lai, J., Sah, D.W.Y. and Porreca, F.: Normalization of Experimental Neuropathic Pain by Systemic Artemin. Nature Medicine, 2003.
Gardell, L.R., Vanderah, T.W., Gardell, S.E., Wang, R., Ossipov, M.H., Lai, J. and Porreca, F.: Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J. Neuroscience, 23(23): 8370-8379, 2003
Vanderah, T.W., Schteingart, C., Trojnar, J., Junien, J-L., Lai, J. and Riviere, P.J-M.: FE200041, A Peripheral Efficacious Kappa Opioid Agonist with Unprecedented Selectivity. JPET, 310(1): 326-333, 2004.
Xie, Y.Y., Herman, D.S., Stiller, C.-O., Gardell, L.R., Ossipov, M.H. Lai, J., Porreca, F. and Vanderah, T.W., Mediation of Opioid-induced Paradoxical Pain and Antinociceptive Tolerance by Cholecystokinin In the Rostral Ventromedial Medulla, J.Neuroscience, 25(2): 409-416, 2005.
Ibrahim MM. Porreca F. Lai J. Albrecht PJ. Rice FL. Khodorova A. Davar G. Makriyannis A. Vanderah TW. Mata HP. Malan TP Jr.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. PNAS USA. 102(8):3093-8, 2005.
Gardell LR. King T. Ossipov MH. Rice KC. Lai J. Vanderah TW. Porreca F. Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neuroscience Letters. 396(1):44-9, 2006
Ibrahim MM. Rude ML. Stagg NJ. Mata HP. Lai J. Vanderah TW. Porreca F. Buckley NE. Makriyannis A. Malan TP Jr. CB2 cannabinoid receptor mediation of antinociception. Pain. 122(1-2):36-42, 2006
F. Porreca, T. W. Vanderah, W. Guo, M. Barth, P. Dodey, V. Peyrou, J. M. Luccarini, J.-L. Junien, and D. Pruneau. Antinociceptive Pharmacology of N-[[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, Fumarate (LF22-0542), a Novel Nonpeptidic Bradykinin B1 Receptor Antagonist, Journal of Pharmacology and Experimental Therapeutics, 318:195-205, 2006.
King T. Rao S. Vanderah T. Chen Q. Vardanyan A. Porreca F. Differential blockade of nerve injury-induced shift in weight bearing and thermal and tactile hypersensitivity by milnacipran. Journal of Pain. 7(7):513-20, 2006 Jul.
Neagus S,S., Vanderah, T.W., Brandt, M.R., Bilsky, E.J., Becerra, L. and Borsook, D. Preclinical Assessment of candidate analgesic drugs: Recent advances and future challenges, Journal of Pharmacology and Experimental Therapeutics, 319:507-514, 2006.