Ronald G. Wiley, M.D., Ph.D.


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Faculty Appointments
Professor of Neurology Professor of Pharmacology
M.D., Northwestern University Feinberg School of Medicine, Chicago, IllinoisPh.D., Pharmacology, Northwestern University, Evanston/Chicago, IllinoisB.S., Honors Program in Medical Education, Northwestern University, Evanston/Chicago, Illinois
Office Address
1310 24th Avenue, South
Nashville, TN C_ERR-OR
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. .
Research Keywords
molecular neurosurgery, animal pain models, targeted toxins, image analysis
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 [print-electronic]. 2007 May 5/25/2007; 146(3): 1333-45. PMID: 17418497, PII: S0306-4522(07)00152-2, DOI: 10.1016/j.neuroscience.2007.01.066, ISSN: 0306-4522.

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 [print-electronic]. 2005 Apr 4/15/2005; 159(1): 89-94. PMID: 15795001, PII: S0166-4328(04)00389-4, DOI: 10.1016/j.bbr.2004.10.005, ISSN: 0166-4328.

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. 2004; 118: 627-35.

Wiley RG, Harrison MB, Levey AI, Lappi DA. Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter. Cell. Mol. Neurobiol. 2003 Oct; 23(4-5): 839-50. PMID: 14514035, ISSN: 0272-4340.

Wiley RG, Lappi DA. Targeted toxins in pain. Adv. Drug Deliv. Rev. 2003 Aug 8/28/2003; 55(8): 1043-54. PMID: 12935943, PII: S0169409X03001029, ISSN: 0169-409X.

Wiley RG. Targeting toxins to neural antigens and receptors. Methods Mol. Biol. 2001; 166: 267-76. PMID: 11217372, ISSN: 1064-3745.

Wiley RG. Toxin-induced death of neurotrophin-sensitive neurons. Methods Mol. Biol. 2001; 169: 217-22. PMID: 11142013, ISSN: 1064-3745.

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.. 2001; 299: 840-8.

Wiley RG, Kline IV RH. Neuronal lesioning with axonally transported toxins. J. Neurosci. Methods. 2000 Nov 11/15/2000; 103(1): 73-82. PMID: 11074097, PII: S0165-0270(00)00297-1, ISSN: 0165-0270.

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. 2000 Nov; 48(2): 285-99. PMID: 11054475, PII: S0008-6363(00)00185-1, ISSN: 0008-6363.

Sachdev RN, Egli M, Stonecypher M, Wiley RG, Ebner FF. Enhancement of cortical plasticity by behavioral training in acetylcholine-depleted adult rats. J. Neurophysiol. 2000 Oct; 84(4): 1971-81. PMID: 11024090, ISSN: 0022-3077.

Wiley RG. Neuropeptide-toxin conjugates in pain research and treatment. Reg Anesth Pain Med. 2000 Sep; 25(5): 546-8. PMID: 11009244, PII: S1098-7339(00)02478-0, DOI: 10.1053/rapm.2000.8457, ISSN: 1098-7339.

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. 2000 May 5/1/2000; 420(2): 211-32. PMID: 10753308, PII: 10.1002/(SICI)1096-9861(20000501)420:2<211::AID-CNE5>3.0.CO;2-3, ISSN: 0021-9967.

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. 2000 Mar; 16(2): 101-13. PMID: 10749156, ISSN: 0740-9303.

Wiley, R.G. and Kline, R.J. Neuronal lesioning with axonally targeted toxins. J. Neurosci. Meth. 2000; 103: 72-83.

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. 2000; 109: 37-47.

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. 2000; 21: 395-403.

Wiley,R.G.,. Neuropeptide-toxin conjugates in pain research and treatment. Reg Anesth. Pain Med. 2000; 25: 546-8.

Wiley RG, Lappi DA. Targeting neurokinin-1 receptor-expressing neurons with [Sar9,Met(O2)11 substance P-saporin. Neurosci. Lett. 1999 Dec 12/17/1999; 277(1): 1-4. PMID: 10643883, PII: S0304-3940(99)00846-0, ISSN: 0304-3940.

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. 1999 Nov 11/20/1999; 847(2): 284-98. PMID: 10575099, PII: S0006-8993(99)02099-5, ISSN: 0006-8993.

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. 1999; 831((1-2)): 322-36.

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. 1999; 847: 284-98.

Wrenn, C.C. and Wiley, R.G. Lack of effect of moderate Purkinje cell loss on working memory. Neuroscience. 1999; 107: 433-335.

Sachdev RN, Lu SM, Wiley RG, Ebner FF. Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J. Neurophysiol. 1998 Jun; 79(6): 3216-28. PMID: 9636120, ISSN: 0022-3077.

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. 1998; 800: 198-206.

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. 1998; 71: 2411-20.

Wiley RG. Findings about the cholinergic basal forebrain using immunotoxin to the nerve growth factor receptor. Ann. N. Y. Acad. Sci. 1997 Dec 12/19/1997; 835: 20-9. PMID: 9616759, ISSN: 0077-8923.

Wiley RG, Lappi DA. Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin in rats. Neurosci. Lett. 1997 Jul 7/18/1997; 230(2): 97-100. PMID: 9259473, PII: S0304-3940(97)00490-4, ISSN: 0304-3940.

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. 1997; 278: 239-24.

Wrenn CC, Picklo MJ, Lappi DA, Robertson D, Wiley RG. Central noradrenergic lesioning using anti-DBH-saporin: anatomical findings. Brain Res. 1996 Nov 11/18/1996; 740(1-2): 175-84. PMID: 8973812, PII: S0006-8993(96)00855-4, ISSN: 0006-8993.

Wiley RG. Targeting toxins to neural antigens and receptors. Semin. Cancer Biol. 1996 Apr; 7(2): 71-7. PMID: 8740562, PII: S1044-579X(96)90011-5, DOI: 10.1006/scbi.1996.0011, ISSN: 1044-579X.

Roberts RC, Strain-Sloum C and Wiley RG. Effects of suicide transport lesions of the striatopallidal or striatonigral pathways on striatal ultrastructure. Brain Res. 1996; 701: 227-37.

Wrenn CC, Picklo MJ, Lappi DA, Robertson DR and Wiley RG. Intraventricular injection of anti-D?H-saporin: Anatomical findings. Brain Res. 1996; 740: 175-86.

Picklo MJ, Wiley RG, Lonce S, Lappi DA, Robertson D. Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats. J. Pharmacol. Exp. Ther. 1995 Nov; 275(2): 1003-10. PMID: 7473126, ISSN: 0022-3565.

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. 1995; 128: 157-61.

Picklo MJ, Wiley RG, Lappi DA, Robertson D. Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin. Brain Res. 1994 Dec 12/15/1994; 666(2): 195-200. PMID: 7882029, PII: 0006-8993(94)90772-2, ISSN: 0006-8993.

Wiley RG. Neural lesioning with ribosome-inactivating proteins: suicide transport and immunolesioning. Trends Neurosci. 1992 Aug; 15(8): 285-90. PMID: 1384197, ISSN: 0166-2236.

Moix LJ, Greeson DM, Armstrong DM, Wiley RG. Separate signals mediate hypoglossal motor neuron response to axonal injury. Brain Res. 1991 Nov 11/8/1991; 564(1): 176-80. PMID: 1723339, PII: 0006-8993(91)91371-7, ISSN: 0006-8993.

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. 1989 Dec 12/25/1989; 505(1): 44-54. PMID: 2575436, PII: 0006-8993(89)90114-5, ISSN: 0006-8993.

Davis TL, Wiley RG. Anti-Thy-1 immunotoxin, OX7-saporin, destroys cerebellar Purkinje cells after intraventricular injection in rats. Brain Res. 1989 Dec 12/18/1989; 504(2): 216-22. PMID: 2574621, PII: 0006-8993(89)91360-7, ISSN: 0006-8993.

Henson JW, Wiley RG. CNS chloromas in patients presenting with eosinophilia. Neurology. 1989 Oct; 39(10): 1386-8. PMID: 2677835, ISSN: 0028-3878.

Wiley RG, Oeltmann TN. Anti-ricin antibody protects against systemic toxicity without affecting suicide transport. J. Neurosci. Methods. 1989 Apr; 27(3): 203-9. PMID: 2725004, ISSN: 0165-0270.

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. 1989 Apr; 12(2): 93-100. PMID: 2650529, ISSN: 0277-3732.

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. 1988 Nov 11/22/1988; 277(4): 578-92. PMID: 3209747, DOI: 10.1002/cne.902770410, ISSN: 0021-9967.

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. 1988 Jul; 264(1): 168-75. PMID: 3164992, PII: 0003-9861(88)90582-6, ISSN: 0003-9861.

LaRocca CD, Wiley RG. Monoclonal anti-Thy 1 antibody (OX7) is axonally transported in rat nervous system. Brain Res. 1988 May 5/24/1988; 449(1-2): 381-5. PMID: 2456131, PII: 0006-8993(88)91059-1, ISSN: 0006-8993.

Wiley RG, Stirpe F. Modeccin and volkensin but not abrin are effective suicide transport agents in rat CNS. Brain Res. 1988 Jan 1/12/1988; 438(1-2): 145-54. PMID: 2449931, PII: 0006-8993(88)91333-9, ISSN: 0006-8993.

Hagenau C, Grosh W, Currie M, Wiley RG. Comparison of spinal magnetic resonance imaging and myelography in cancer patients. J. Clin. Oncol. 1987 Oct; 5(10): 1663-9. PMID: 3655863, ISSN: 0732-183X.

Onrot J, Wiley RG, Fogo A, Biaggioni I, Robertson D, Hollister AS. Neck tumour with syncope due to paroxysmal sympathetic withdrawal. J. Neurol. Neurosurg. Psychiatr. 1987 Aug; 50(8): 1063-6. PMID: 3655815, PMCID: PMC1032240, ISSN: 0022-3050.

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).

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: 1054-62.

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.

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: 322-6.

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.