Biomedical Research Education & Training
Faculty Member

Wiley, Ronald G., M.D., Ph.D.
Professor of Neurology
Professor of Pharmacology

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Phone Number: (615) 327-4751 ext. 5244

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Wiley, Ronald's picture
Academic history
B.S., Northwestern University, Evanston, IL
Ph.D., Northwestern University, Evanston, IL
M.D., Northwestern University, Evanston, IL

Office Address   Mailing Address

Room F429 VA ACRE Building


Research Keywords
Immunotoxins, neurobiology of pain, neural phenotyping, animal behavior, neuro-anatomy,Neuroscience,Pharmacology,Physiology,Receptor

Patient Care Specialty
General neurology - central and peripheral; neuro-oncology; pain, particularly neuropathic pain

Research Specialty
molecular neurosurgery, animal pain models, targeted toxins, image analysis

Research Description
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. .

Clinical Interests
Cancer, pain

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, 277, R1063-1075

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., 831, 322-326

Wrenn,C.C. and Wiley,R.G., . The behavioral functions of the cholinergic basal forebrain: lessons from 192 IgG-saporin, .. Int. J. Dev.Neurosci.,, 16, 595-602

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., 10, 1054-1062

. 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).

. 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, 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, 118, 627-635, 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., 299, 840-848, 2001

Wiley, RG. Targeting toxins to neural antigens and receptors. Methods Mol Biol, 166, 267-76, 2001

Wiley, RG. Toxin-induced death of neurotrophin-sensitive neurons. Methods Mol Biol, 169, 217-22, 2001

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, 21, 395-403, 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

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, 109, 37-47, 2000

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

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, 103, 72-83, 2000

Wiley, RG. Neuropeptide-toxin conjugates in pain research and treatment. Reg Anesth Pain Med, 25(5), 546-8, 2000

Wiley, RG, Kline IV, RH. Neuronal lesioning with axonally transported toxins. J Neurosci Methods, 103(1), 73-82, 2000

Wiley,R.G., . Neuropeptide-toxin conjugates in pain research and treatment, . Reg Anesth. Pain Med, 25, 546-548, 2000

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. and Wiley, R.G. Lack of effect of moderate Purkinje cell loss on working memory. Neuroscience, 107, 433-335, 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, 847, 284-298, 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, 71, 2411-2420, 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, 800, 198-206, 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, 278, 239-24, 1997

Wiley, RG. Findings about the cholinergic basal forebrain using immunotoxin to the nerve growth factor receptor. Ann N Y Acad Sci, 835, 20-9, 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

Roberts RC, Strain-Sloum C and Wiley RG . Effects of suicide transport lesions of the striatopallidal or striatonigral pathways on striatal ultrastructure. Brain Res, 701, 227-237, 1996

Wiley, RG. Targeting toxins to neural antigens and receptors. Semin Cancer Biol, 7(2), 71-7, 1996

Wrenn CC, Picklo MJ, Lappi DA, Robertson DR and Wiley RG. Intraventricular injection of anti-D?H-saporin: Anatomical findings. Brain Res, 740, 175-186 , 1996

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

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, 128, 157- 161, 1995

Wiley RG and Lappi DA. Suicide Transport and Immunolesioning. R.G. Landes Co.: Austin, TX 1994.

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

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

Henson, JW, Wiley, RG. CNS chloromas in patients presenting with eosinophilia. Neurology, 39(10), 1386-8, 1989

Wiley, RG, Oeltmann, TN. Anti-ricin antibody protects against systemic toxicity without affecting suicide transport. J Neurosci Methods, 27(3), 203-9, 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

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

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

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 PMCID:1032240

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