Ronald G. Wiley, M.D., Ph.D.
Professor of Neurology, Pharmacology
Vanderbilt University Medical Center
4A-105D Veterans Administration Medical Center
Nashville, TN 37232
molecular neurosurgery, animal pain models, targeted toxins, image analysis
The Laboratory of Experimental Neurology in the ACRE building of the Nashville VA Medical Center is devoted to the neurobiology of pain. A key feature of our approach is the use of targeted cytotoxins to selectively destroy specific types of neurons. This strategy has evolved in our laboratory from initial use of the toxic lectins, ricin, abrin, modeccin and volkensin, as suicide transport agents that kill any neuron they are applied to. We subsequently developed selective agents such as immunotoxins that consist of a monoclonal antibody directed against a neuronal surface molecule, armed to kill by conjugation with the ribosome inactivating protein, saporin. The immunotoxins, 192 IgG-saporin, anti-DBH-saporin, anti-DAT-saporin, etc. are effective immunolesioning agents that destroy specific classes of neurons determined by the presence of target molecules on the cell surface. These immunotoxins have been used extensively for studies of learning and memory, and now, are also of interest in pain experiments. More recently, neuropeptides have been used to target saporin, including substance P and dermorphin, which are toxic to cells expressing substance P receptors or mu opiate receptors, respectively.
Our approach includes the development, validation and use of operant behavioral tests of thermal pain perception in addition to standard reflex assays (hotplate, tail flick) in order to assess the affective/motivation component of pain. Animals trained on the operant tests are injected with targeted toxin to eliminate a specific class of neurons in a specific location such as the dorsal horn of the lumbar spinal cord and then retested to detect changes in behavioral responses to noxious heat and responses to analgesic drugs or other agents that alter pain sensitivity. At the completion of behavioral testing, the toxin-induced cell loss is assessed using immunohistochemistry and image analysis techniques to quantitatively relate the extent of lesion in each animal to the behavioral observations from the same animal. Functional anatomic analyses are also performed using induction of c-fos expression as an indication of neuronal activation by noxious stimuli. The goal is better understanding of the role(s) of specific types of neurons in nociception and analgesic drug action, and discovery of new approaches to treat chronic pain. .
- de Lacalle,S., Kulkarni,S., and Wiley,R.G., "Lesion-induced transneuronal plasticity of the cholinergic innervation in the adult rat entorhinal cortex,.." Eur. J. Neurosci., 101054-1062, .
- Wrenn,C.C. and Wiley,R.G., "The behavioral functions of the cholinergic basal forebrain: lessons from 192 IgG-saporin, .." Int. J. Dev.Neurosci.,, 16595-602, .
- Madden,C.J., Ito,S., Rinaman,L., Wiley,R.G., and Sved,A.F., "Lesions of the C1 catecholaminergic neurons of the ventrolateral medulla in rats using anti-DbetaH-saporin,." Am. J. Physiol, 277R1063-1075, .
- Milner,T.A., Hammel,J.R., Ghorbani,T.T., Wiley,R.G., and Pierce,J.P., "Septal cholinergic deafferentation of the dentate gyrus results in a loss of a subset of neuropeptide Y somata and an increase in synaptic area on remaining neuropeptide Y dendrites,." Brain Res., 831322-326, .
- "Vierck, C.J., Jr., Kline, R.H., IV and Wiley, R.G.: Intrathecal substance P-saporin attenuates operant escape from nociceptive thermal stimuli, Neuroscience, 119:223-232, 2003." , .
- "WILEY, R.G., Harrison, M.B., Levey, A.I. & Lappi, D.A.: Selective destruction of midbrain dopaminergic neurons using immunotoxin to the dopamine transporter, Cell.Molec.Neurobiol., 2003 (in press)." , .
- Wiley, RG, Kline, RH, Vierck, CJ Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: behavioral and anatomical analyses. Neuroscience, 146(3), 1333-45, 2007.
- May, ME, Harvey, MT, Valdovinos, MG, Kline, RH, Wiley, RG, Kennedy, CH Nociceptor and age specific effects of REM sleep deprivation induced hyperalgesia. Behav Brain Res, 159(1), 89-94, 2005.
- Vierck, C.J., Kline, R.H. and Wiley, R.G., "Comparison of operant escape and innate reflex responses to nociceptive skin temperatures produced by heat and cold stimulation of rats.." Behav.Neurosci, 118627-635, 2004.
- Wiley, RG, Harrison, MB, Levey, AI, Lappi, DA Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter. Cell Mol Neurobiol, 23(4-5), 839-50, 2003.
- Wiley, RG, Lappi, DA Targeted toxins in pain. Adv Drug Deliv Rev, 55(8), 1043-54, 2003.
- Vogt, L.J., Sim-Selley, L.J., Childers, S.R., Wiley, R.G. and Vogt, B.A "Colocalization of mu-opioid receptors and activated G-proteins in rat cingulate cortex." J.Pharmacol.Exp.Therap., 299840-848, 2001.
- Wiley, RG Targeting toxins to neural antigens and receptors. Methods Mol Biol, 166267-76, 2001.
- Wiley, RG Toxin-induced death of neurotrophin-sensitive neurons. Methods Mol Biol, 169217-22, 2001.
- Sachdev, RN, Egli, M, Stonecypher, M, Wiley, RG, Ebner, FF Enhancement of cortical plasticity by behavioral training in acetylcholine-depleted adult rats. J Neurophysiol, 84(4), 1971-81, 2000.
- Schroeter, S, Apparsundaram, S, Wiley, RG, Miner, LH, Sesack, SR, Blakely, RD Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter. J Comp Neurol, 420(2), 211-32, 2000.
- Gandhi,C.C., Kelly1 RM, Wiley,R.G., and Walsh,T.J., "Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin,." Behav. Brain Res, 10937-47, 2000.
- Shin, HG, Barnett, JV, Chang, P, Reddy, S, Drinkwater, DC, Pierson, RN, Wiley, RG, Murray, KT Molecular heterogeneity of protein kinase C expression in human ventricle. Cardiovasc Res, 48(2), 285-99, 2000.
- Wiley, R.G. and Kline, R.J "Neuronal lesioning with axonally targeted toxins." J. Neurosci. Meth, 10372-83, 2000.
- Wiley, RG, Kline IV, RH Neuronal lesioning with axonally transported toxins. J Neurosci Methods, 103(1), 73-82, 2000.
- Wiley, RG Neuropeptide-toxin conjugates in pain research and treatment. Reg Anesth Pain Med, 25(5), 546-8, 2000.
- Wiley,R.G., "Neuropeptide-toxin conjugates in pain research and treatment,." Reg Anesth. Pain Med, 25546-548, 2000.
- Angner,R.T., Kelly,R.M., Wiley,R.G., Walsh,T.J., and Reuhl,K.R., "Preferential destruction of cerebellar Purkinje cells by OX7-saporin,." Neurotoxicology, 21395-403, 2000.
- Fezza, JP, Howard, J, Wiley, R, Wesley, RE, Klippenstein, K, Dettbarn, W The effects of tetanus toxin on the orbicularis oculi muscle. Ophthal Plast Reconstr Surg, 16(2), 101-13, 2000.
- Wrenn, C.C. and Wiley, R.G "Lack of effect of moderate Purkinje cell loss on working memory." Neuroscience, 107433-335, 1999.
- Milner TA, Hammel JR, Ghorbani TT, Wiley RG and Pierce JP "Septal cholinergic deafferentation of the dentate gyrus results in a loss of a subset of neuropeptide Y somata and an increase in synaptic area on remaining neuropeptide Y dendrites." Brain Res, 831(1-2), 322-336, 1999.
- Wiley, RG, Lappi, DA Targeting neurokinin-1 receptor-expressing neurons with [Sar9,Met(O2)11 substance P-saporin. Neurosci Lett, 277(1), 1-4, 1999.
- Wrenn, C.C., Lappi, D.A. & WILEY, R.G "Threshold relationship between lesion extent of the cholinergic basal forebrain in the rat and working memory impairment in the radial maze." Brain Research, 847284-298, 1999.
- Wrenn, CC, Lappi, DA, Wiley, RG Threshold relationship between lesion extent of the cholinergic basal forebrain in the rat and working memory impairment in the radial maze. Brain Res, 847(2), 284-98, 1999.
- Gilmor,M.L., Counts,S.E., Wiley,R.G., and Levey,A.I., "Coordinate expression of the vesicular acetylcholine transporter and choline acetyltransferase following septohippocampal pathway lesions,." J. Neurochem, 712411-2420, 1998.
- Sachdev, RN, Lu, SM, Wiley, RG, Ebner, FF Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J Neurophysiol, 79(6), 3216-28, 1998.
- Zhang,Z.J., Lappi,D.A., Wrenn,C.C., Milner,T.A., and Wiley,R.G., "Selective lesion of the cholinergic basal forebrain causes a loss of cortical neuropeptide Y and somatostatin neurons." Brain Res, 800198-206, 1998.
- Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters R S, Lappi DA, Wiley RG and Simone DA "Ablation of lamina I spinal neurons expressing the substance P receptor profoundly inhibits yperalgesia." Science, 278239-24, 1997.
- Wiley, RG, Lappi, DA Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin in rats. Neurosci Lett, 230(2), 97-100, 1997.
- Wiley, RG Findings about the cholinergic basal forebrain using immunotoxin to the nerve growth factor receptor. Ann N Y Acad Sci, 83520-9, 1997.
- Wrenn, CC, Picklo, MJ, Lappi, DA, Robertson, D, Wiley, RG Central noradrenergic lesioning using anti-DBH-saporin: anatomical findings. Brain Res, 740(1-2), 175-84, 1996.
- Roberts RC, Strain-Sloum C and Wiley RG "Effects of suicide transport lesions of the striatopallidal or striatonigral pathways on striatal ultrastructure." Brain Res, 701227-237, 1996.
- Wrenn CC, Picklo MJ, Lappi DA, Robertson DR and Wiley RG "Intraventricular injection of anti-D?H-saporin: Anatomical findings." Brain Res, 740175-186 , 1996.
- Wiley, RG Targeting toxins to neural antigens and receptors. Semin Cancer Biol, 7(2), 71-7, 1996.
- Picklo, MJ, Wiley, RG, Lonce, S, Lappi, DA, Robertson, D Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats. J Pharmacol Exp Ther, 275(2), 1003-10, 1995.
- Wiley RG, Berbos TG, Deckwerth T, Johnson EM, Jr. and Lappi DA "Destruction of the cholinergic basal forebrain using immunotoxin to rat NGF receptor: Modeling the cholinergic degeneration of Alzheimer's disease." J Neurol Sci, 128157- 161, 1995.
- Picklo, MJ, Wiley, RG, Lappi, DA, Robertson, D Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin. Brain Res, 666(2), 195-200, 1994.
- Wiley, RG Neural lesioning with ribosome-inactivating proteins: suicide transport and immunolesioning. Trends Neurosci, 15(8), 285-90, 1992.
- Moix, LJ, Greeson, DM, Armstrong, DM, Wiley, RG Separate signals mediate hypoglossal motor neuron response to axonal injury. Brain Res, 564(1), 176-80, 1991.
- Davis, TL, Wiley, RG Anti-Thy-1 immunotoxin, OX7-saporin, destroys cerebellar Purkinje cells after intraventricular injection in rats. Brain Res, 504(2), 216-22, 1989.
- Wiley, RG, Oeltmann, TN Anti-ricin antibody protects against systemic toxicity without affecting suicide transport. J Neurosci Methods, 27(3), 203-9, 1989.
- Henson, JW, Wiley, RG CNS chloromas in patients presenting with eosinophilia. Neurology, 39(10), 1386-8, 1989.
- Wiley, RG, Stirpe, F, Thorpe, P, Oeltmann, TN Neuronotoxic effects of monoclonal anti-Thy 1 antibody (OX7) coupled to the ribosome inactivating protein, saporin, as studied by suicide transport experiments in the rat. Brain Res, 505(1), 44-54, 1989.
- Grote, TH, Grosh, WW, List, AF, Wiley, R, Cousar, JB, Johnson, DH Primary lymphoma of the central nervous system. A report of 20 cases and a review of the literature. Am J Clin Oncol, 12(2), 93-100, 1989.
- Wall, JT, Cusick, CG, Migani-Wall, SA, Wiley, RG Cortical organization after treatment of a peripheral nerve with ricin: an evaluation of the relationship between sensory neuron death and cortical adjustments after nerve injury. J Comp Neurol, 277(4), 578-92, 1988.
- Wiley, RG, Stirpe, F Modeccin and volkensin but not abrin are effective suicide transport agents in rat CNS. Brain Res, 438(1-2), 145-54, 1988.
- LaRocca, CD, Wiley, RG Monoclonal anti-Thy 1 antibody (OX7) is axonally transported in rat nervous system. Brain Res, 449(1-2), 381-5, 1988.
- Ovadia, M, Wiley, RG, Hager, C, LaRocca, C, Oeltmann, TN Synthesis and in vitro and in vivo activity of a hybrid composed of ricin B chain-barley ribosome-inactivating protein. Arch Biochem Biophys, 264(1), 168-75, 1988.
- Hagenau, C, Grosh, W, Currie, M, Wiley, RG Comparison of spinal magnetic resonance imaging and myelography in cancer patients. J Clin Oncol, 5(10), 1663-9, 1987.
- Onrot, J, Wiley, RG, Fogo, A, Biaggioni, I, Robertson, D, Hollister, AS Neck tumour with syncope due to paroxysmal sympathetic withdrawal. J Neurol Neurosurg Psychiatry, 50(8), 1063-6, 1987.