Physiology Home > People > Faculty >
BRADLEY K. TAYLOR, Ph.D.
Ph.D. University of California, San Francisco
Office: MS-605 Medical Center 0298
Tel: (859) 323-1870
The Neurobiology and Pharmacology of Chronic Pain
Our laboratory investigates the mechanisms through which inflammation or nerve injury produces changes in the spinal cord and brain, leading to a transition from acute pain to chronic pain. The hallmark of our work is its multidisciplinary approach: we use pharmacological, behavioral, molecular, neuroanatomical and neurophysiological analyses to discover and validate new pharmacotherapeutic targets in preparation for clinical trials.
Our long-term goal is to generate innovative ideas and clinically significant data that will contribute to a new pharmacotherapy of chronic pain. To achieve this, our projects emphasize the following neural receptor systems:
- opioid (µ, δ, and κ)
- neuropeptide Y (Y1 and Y2)
- peroxisome proliferator-activated receptor gamma (PPARγ)
- sphingosine-1-phosphate 1 (S1P1)
- cannabinoid CB2
We take a systems approach to better understand the neurobiology and pharmacology of chronic pain. Thus, we study the transmission of nociceptive (pain) signals at several levels of the neuraxis:
- Somatosensory neurons (primary afferent nociceptor)
- Spinal Cord (superficial laminae of the dorsal horn)
- Brain (locus coeruleus, nucleus raphe magnus, amygdala)
The mechanisms and pharmacology of chronic pain vary with the syndrome or disease state. We focus on the following problems, all of which dramatically reduce quality of life:
- Neuropathic pain after traumatic nerve injury
- Painful Diabetic Neuropathy
- Pain of chronic inflammation
- Pain of Multiple Sclerosis
- Suzanne Doolen, PhD, Scientist III
- Renee Donahue, MS, Scientist III
- Julio Morales-Medina, Postdoctoral Fellow
- Gregory Corder, PhD candidate
- Ryan Griggs, PhD candidate
- Weisi Fu, PhD candidate
- Justin Pinson, research assistant
Active Research Projects (5)
1. Tonic inhibition of chronic inflammatory and neuropathic pain by NPY
Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npytet/tet) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity (Figure 1). Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown. These and other data establish spinal NPY receptor systems as an endogenous braking mechanism that exerts a tonic, long-lasting, broad-spectrum inhibitory control of spinal nociceptive transmission, thus impeding the transition from acute to chronic pain. NPY and its receptors appear to be part of a mechanism whereby mammals naturally recover from the hyperalgesia associated with inflammation or nerve injury. Studies are underway to determine the molecular mechanisms underlying the endogenous inhibition of chronic pain by NPY.
Special Methodologies: Conditional NPYtet deletion mutant mice, functional NPY receptor-G-protein [35S]GTPγS binding assays, NK1 internalization assays, Viral vector-mediated gene delivery of NPY and NPY receptors.
Funding: R01 NINDS45954, Taylor (PI) 2002-2014, Neuropeptidergic Inhibition of Spinal Pain Transmission
Figure 1. Doxycycline potentiates behavioral signs of neuropathic pain in Npytet/tet mice. Yellow boxes denote the time periods when mice received Doxycycline in the drinking water, relative to peripheral nerve injury. Spared nerve injury (SNI) produced some cold allodynia within 10 days. Compared to control conditions (blue squares), conditional NPY knockdown (red circles) dramatically increased cold allodynia in a reversible and repeatable manner.
From Solway et al, Proceedings of the National Academy of Sciences 108:7224-9 (2011).
2. PPARγ and Painful Diabetic Neuropathy
Over 25 million adults and children in the U.S. have diabetes. Approximately a quarter of diabetics suffer from painful diabetic neuropathy (PDN), characterized by deep aching and hyperalgesia. Because current pharmacological treatments yield pain relief in less than 50% of these patients, and of those, the pain relief is less than 50%, we are searching for new pharmacotherapeutic targets. We found that activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the spinal cord reduces various forms of neuropathic pain, including PDN. Figure 2 illustrates that the FDA-approved PPARγ agonist pioglitazone reduces the development of cutaneous hypersensitivity associated with traumatic nerve damage. Current studies in rat and mouse models of type II diabetes are investigating the mechanisms of PDN and its inhibition by spinal PPARγ.
Special Methodologies: ZDF rat and db/db mouse models of type II diabetes and painful diabetic neuropathy; conditioned place preference; mechanical conflict avoidance system.
- R01 NINDS 062306, Taylor (PI), 2008-2013, “PPAR gamma Inhibition of Spinal Pain Transmission”
- F31 NINDS , Taylor (sponsor to R. Griggs) 2013-2015, “Methylglyoxal and TRPA1 contribution to neuropathic pain in type 2 diabetes ”
Figure 2. The development of nerve injury-induced hypersensitivity is reduced by pioglitazone.Pain-related responses to plantar application of von Frey hairs (A), acetone (B), or pin prick (C) were monitored from 7 d prior to 6 wk after spared nerve injury (SNI, t = 0 d, arrow). After baseline measurements, pioglitazone (mixed with rat chow in concentrations yielding daily doses of 0 to 30 mg/kg/day) was administered throughout the rest of the study (yellow bars). Oral pioglitazone dose-dependently reduced the development of hypersensitivity (n = 8-9). Values represent mean ± SEM. Statistical significance (p<0.05 by Bonferroni post-tests after repeated measures 2-way ANOVA) between vehicle and high («), high + medium (†), or high + medium + low (‡) doses of pioglitazone.
From Morgenweck, Griggs, Donahue et al, Neuropharmacology (2013, in press).
3. Opioid inhibition of chronic pain
The development of pathological pain arises from injury-induced maladaptive plasticity within the central nociceptive circuitry, resulting in amplification of synaptic efficacy. While NMDA-mediated long-term potentiation is argued to maintain a long-lived facilitation of spinal nociceptive transmission, or pain memory trace, we know little of its modulation. Following sustained noxious input, opioids orchestrate an adaptive compensatory response that modulates neuronal excitability and fine-tunes spinal glutamatergic nociceptive transmission via pre- and post-synaptic mechanisms. To investigate the mechanisms of long-lived central sensitization and its opioid inhibition, we developed a new mouse model that transiently develops cutaneous hypersensitivity, which resolves within 21 days (left of the vertical dash of the left panel of Fig 3). After resolution of behavioral signs of inflammatory nociception, we then administered naltrexone, an opioid receptor antagonist. As illustrated by the red line of Figure 3, naltrexone produced a dramatic reinstatement of hypersensitivity, and this is accompanied by phosphorylation of the transcription factor ERK, a marker of spinal nociceptive neuron activation (right panels of Figure 3). Current studies are evaluating the mechanisms that underlie long-term latent nociceptive sensitization, and its inhibition by opioids. We are also extending our studies to experimental and postoperative pain models in humans.
Special Methodology: Transgenic mice, conditioned place preference, experimental clinical pain models, functional mu-opioid receptor-G-protein [35S]GTPγS binding assays.
Funding: F31 NIDA 032496, Taylor (sponsor to G. Corder) 2012-2014, “Prolonged activation of endogenous opioid analgesia after inflammation”
Figure 3. Naltrexone reinstates hyperalgesia in an NMDA receptor-dependent manner.
From Corder et al.
4. Multiple Sclerosis and S1P and CB2 receptors.
Multiple sclerosis (MS) is an autoimmune-inflammatory neurodegenerative disease of the CNS, characterized by focal areas of demyelination. Approximately half of MS patients report pain, and this is particularly debilitating in primary-progressive and progressive-relapsing forms. Despite this, we know little of the mechanisms that induce or maintain MS pain, and so can offer little in the way of pain relief. Pain-related complaints include allodynia and hyperalgesia at the extremities, and these we have modeled in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We are currently using a multidisciplinary approach (including Ca imaging in spinal cord slices, Fig 4) to test the hypotheses that inhibition of sphingosine-1-phosphate (S1P) and activation of cannabinoid 2 (CB2) receptors in the spinal cord will reduce behavioral and molecular signs of chronic pain in MS.
Special Methodology: 7 Tesla MRI imaging of the rodent spinal cord.
Funding: Canadian Institutes of Health Research, Taylor (co-PI) 2012-2015, “Targeting amino acid and biogenic amine neurotransmitters to improve functional outcomes in EAE”
Figure 4. Multiple sclerosis increases neuronal sensitivity in the dorsal horn. Peak glutamate-evoked Ca2+ responses in dorsal horn slices from control mice and mice treated with myelin oligodendrocyte glycoprotein 33-55 (MOG, a model of multiple sclerosis). Slices were prepared from 5 wk mice, 7–10 d after initial MOG treatment. Ca2+responses were evoked by a 10 s exposure to glutamate at concentrations indicated. Data represent average ± SEM from 5 slices. **P<0.01, ***P<0.001.
From Doolen et al
5. Synaptic plasticity in the dorsal horn
Central sensitization refers to an increase in the excitability of neurons within the spinal cord, such that sensory inputs produce increased responses and chronic pain. Our long term goal is to understand the mechanisms that lead to injury-induced central sensitization and to establish ameliorative therapeutic targets for chronic pain. Central sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We use Fura-2AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ . We found that exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice. Figure 5 illustrates that the magnitude of glutamate-evoked Ca2+ responses increases in the setting of peripheral neuropathic pain. Current studies are evaluating the contribution of glutamate receptors (AMPA) to central sensitization, and their inhibition by opioids.
Special Methodology: Fura-2 fluorescent Ca2+ imaging in adult spinal cord slices
Funding: R03 NINDS NS77193, Taylor (collaborator to S. Doolen, PI) 2012-2014, “Glutamate-evoked calcium signaling in spinal cord after nerve injury”
Figure 5. Calcium imaging in adult mouse spinal cord slices. Ratiometric images of dorsal horn before (A) and during (B) a 10 s exposure to 1 mM glutamate. Pseudocolor images show values of the 340/380 ratio where blue indicates basal Ca2+ levels and green/red indicate a glutamate-evoked Ca2+ increase. C. Glutamate-evoked Ca2+ traces evoked in panels A and B. The right panel shows that SNI increased glutamate-evoked Ca2+ transients in dorsal horn slices. Slices were prepared from 5 wk mice 7-10 d after sham or SNI surgery.
From Doolen et al, Molecular Pain (2012).
EDUCATIONAL and PROFESSIONAL HISTORY of Dr. Taylor
As of January 2013, Dr Taylor has published 46 peer-reviewed research articles (37 as first or last author) and 11 review articles and book chapters, has chaired 5 symposia at domestic and international meetings, served continuously on the Somatosensory and Chemosensory study section of NIH from 2005-2010, and is an Associate Editor of the journals PAIN and PLoS One.
1991 Ph.D. University of California, San Diego (Pharmacology)
1986 B.S. University of California, Davis (Biochemistry)
Postgraduate training and visiting scientist appointments
- 2005 Visiting Scientist, University of Arizona Arthritis Center (Oct 2005-Jan 2006)
- 1992-1995 Postdoctoral Fellow (with A. Basbaum), University of California-San Francisco
- 2010-present Professor in Physiology, University of Kentucky Medical Center
2011-present Adjunct Professor, Spinal Cord and Brain Injury Research Center at UK
2008-2010 Associate Professor with tenure in Physiology, Univ of Kentucky Medical Center
2006-2008 Associate Professor in Anesthesiology, Tulane University
2004-2008 Associate Professor in Pharmacology (tenured), Tulane University
2002-2004 Assistant Professor in Pharmacology (tenure-track), Tulane University
1999-2002 Assistant Professor in Pharmacology (tenure-track), University of Missouri-KC
1995-1999 Assistant Research Professor, School of Medicine, Univ of Calif-San Francisco
Honors and Awards
2013 Chair, NIH study section IFCN-C
2007-2012 NIH Independent Scientist Award (NIDA)
2006-2010 Regular member, NIH study section SCS (Grants: R01/R03/R15/R21)
2005-2012 NIH study section F02B (Fellowships: Sensory/Motor/Cognitive Neurosci)
Selected Publications as of January 2013
47. Morgenweck, J., Griggs, R.B., Donahue, R.R., Zadina, J.E., and Taylor, B.K. Peroxisome proliferator-activated receptor γ blocks development and reduces established neuropathic pain in rats. Neuropharmacology (in press).
46. Doolen, S.D., Smith, B.N, and Taylor, B.K. Peripheral nerve injury increases glutamate-evoked calcium mobilization in adult spinal cord neurons. Molecular Pain 8: 56 (2012) PMID 22839304
45. Gregus, A.M, Doolen, S. , Dumlao, D.S., Buczynski, M.W., Takasusuki, T., Fitzsimmons, B.L., Hua, X-Y, Taylor, B.K., Dennis, E.A., Yaksh, T.L. Spinal 12-lipoxygenase-derived Hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors. Proceedings of the National Academy of Sciences 109:6721-6 (2012).
44. Solway, B., Bose, S., Corder, G., Donahue, R., and Taylor, B.K. Tonic inhibition of chronic pain by Neuropeptide Y. Proceedings of the National Academy of Sciences 108:7224-9 (2011).
42. Morgenweck, J., Abdel-Aleem, O., McNamara, K.C., Donahue, R.R., Badr, M.Z., and Taylor, B.K. Activation of peroxisome proliferator-activated receptor γ in brain inhibits cutaneous edema and inflammatory pain. Neuropharmacology 58:337-45 (2010). PMC2813335.
41. Corder., G., Siegel, A., Intondi, A.B., Zhang, X., Zadina, J.E., and Taylor, B.K. A novel method to quantify histochemical changes throughout the mediolateral axis of the substantia gelatinosa after spared nerve injury: characterization with TRPV1 and substance P. Journal of Pain 11:388-98 (2010). PMC2872064.
40. Intondi, A.B., Zadina, J.E., Zhang, X., and Taylor, B.K. Topography and time course of changes in spinal neuropeptide Y immunoreactivity after spared nerve injury. Neuroscience 165:914-22 (2010). PMC2815121.
39. Gould, H.J., Garrett, C., Donahue, R.R., Paul, D., Diamond, I., and Taylor, B.K. Ranolazine attenuates behavioral signs of neuropathic pain. Behav. Pharmacol. 20:755-8 (2009). Epub 2009 Sep21. PMID:19773645.
38. Brightwell, J.J. and Taylor, B.K. Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience 160:174-85 (2009). Epub 2009 Feb14 PMC2677992.
37. Kuphal, K.E., Solway, B., Pedrazzini, T., and Taylor, B.K. Y1 receptor knockout increases nociception and prevents the anti-allodynic actions of NPY. Nutrition 24:885-91 (2008). PMC2556173.
36. Churi, S.B., Abdel-Aleem, O., and Taylor, B.K. Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor γ to rapidly inhibit neuropathic pain. J. Pain 9:639-649 (2008). PMC2556259.
34. Intondi, A.B., Dahlgren, M., Eilers, M., and Taylor, B.K. Intrathecal neuropeptide Y reduces behavioral and molecular markers of inflammatory and neuropathic pain. Pain 137:352-65 (2008). PMC2556181.
33. Kuphal, K. and Taylor, B.K. Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents. J. Pain: 8:989-97 (2007).
32. Taylor, B.K., Abhyankar, S.S., Vo, N.T., Kriedt C.L., Churi, SB. and Urban, JH. Neuropeptide Y acts at Y1 Receptors in the Rostral Ventral Medulla to Inhibit Neuropathic Pain. Pain 131:83-95 (2007). PMC2077302.
31. Smith, P.A., Moran, T.D., Abdulla, F., Tumber, K., and Taylor, B.K. Spinal Mechanisms of NPY Analgesia. Peptides: 28:464-74 (2007).
27. Taylor, B.K., Kriedt, C., Nagalingam, S., Dadia, N., and Badr, M. Central administration of perfluorooctanoic acid inhibits cutaneous inflammation. Inflammation Research 54:1-8 (2005).
26. Afrah, A.W., Gustafsson, H., Olgart, L., Brodin, E., Stiller, C-O., and Taylor, B.K. Capsaicin-evoked substance P release in rat dorsal horn increases after peripheral inflammation: a microdialysis study. Neuroscience Letters 368:226-230 (2004).
25. Mahinda, T.B. and Taylor, B.K. Intrathecal Neuropeptide Y inhibits Behavioral and Cardiovascular Responses to Noxious Inflammatory Stimuli in Awake Rats. Physiology and Behavior 80(5): 703-711 (2004).
24. Mahinda, T.B., Lovell, B., and Taylor, B.K. Morphine-Induced Analgesia, Hypotension, And Bradycardia Are Enhanced In Hypertensive Rats. Anesthesia and Analgesia 98(6): 1698-704 (2004).
23. Taylor, B.K. and McCarson, K.E. Neurokinin-1 Receptor Gene Expression in the Mouse Dorsal Horn Increases with Neuropathic Pain. Journal of Pain 5(2):71-6 (2004).
22. Taylor, B.K., Joshi, C.A, and Uppal, H. Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain. Brain Research987(2):135-143 (2003).
21. Taylor, B.K. and Basbaum, A.I. Systemic Morphine-induced Release of Serotonin in the Rostroventral Medulla is not mimicked by Morphine Microinjection into the Periaqueductal Gray. Journal of Neurochemistry 86:1129 (2003).
20. Taylor, B.K., Dadia, N., Yang, C.B., Krishnan, S., and Badr, M. Peroxisome proliferator-activated receptor agonists inhibit inflammatory edema and hyperalgesia, Inflammation 26:121-7 (2002).
19. Taiwo, O.B. and Taylor, B.K. Antihyperalgesic Effects of Intrathecal Neuropeptide Y during Inflammation are Mediated by Y1 Receptors. Pain 96:353-363 (2002).
17. Taylor, B.K., Roderick, R.E., St. Lezin, E., and Basbaum, A.I. Hypoalgesia and hyperalgesia with inherited hypertension in the rat. American Journal of Physiology (Regulatory and Integrative Physiology) 280:R345-54 (2001).
16. Taylor, B.K., Roderick, R.E, and Basbaum, A.I. Brainstem noradrenergic control of nociception is abnormal in the spontaneously hypertensive rat. Neuroscience Letters 291: 139-142 (2000).
15. Taylor, B.K. and Basbaum, A.I. Early antinociception delays edema but does not reduce the magnitude of persistent pain in the formalin test. Journal of Pain, 1:218-228 (2000).
14. Taylor, B.K., Peterson, M.A., Roderick, R.E, Tate, J., Green, P.G., Levine, J.O, Basbaum, A.I. Opioid inhibition of formalin-induced changes in plasma extravasation and local blood flow in rats. Pain, 84:263-270 (2000).
13. Bhatnagar, S., Dallman, M., Basbaum, A.I., and Taylor, B.K. The effects of prior chronic stress on cardiovascular responses to acute restraint and formalin injection. Brain Research 797: 313-320 (1998).
12. Taylor, B.K., Akana, S.F., Peterson, M.A., Dallman, M.F., and Basbaum, A.I. Pituitary-adrenocortical responses to persistent noxious stimuli in the awake rat: Endogenous corticosterone does not reduce pain in the formalin test. Endocrinology 139: 2407-2413 (1998).
11. Peterson, M.A., Basbaum, A.I., Abbadie, C., Rohde, D.S., McKay, W.R, and Taylor, B.K. The differential contribution of capsaicin-sensitive afferents to behavioral and cardiovascular measures of brief and persistent nociception and to Fos expression in the formalin test. Brain Research 755:9-16 (1997).
10. Taylor, B.K., Peterson, M.A., and Basbaum, A.I. Early nociceptive events contribute to the temporal profile, but not the magnitude, of the tonic response to subcutaneous formalin. Journal of Pharmacology and Experimental Therapeutics, 280:876-883 (1997).
9. Abbadie, C., Taylor, B.K., Peterson, M.A., and Basbaum, A.I. Differential contribution of the two phases of the formalin test to the pattern of c‑fos expression in the rat spinal cord: studies with remifentanil and lidocaine. Pain 69: 101-110 (1997).
8. Taylor, B.K., Peterson, M.A., and Basbaum, A.I. Continuous intravenous infusion of naloxone does not change behavioral, cardiovascular or inflammatory responses in the formalin test in the rat. Pain 69: 171-177 (1997).
7. Taylor, B.K. and Printz, M.P. Habituation of airpuff-elicited cardiovascular responses in the Spontaneously Hypertensive Rat. Physiology and Behavior 60: 919-925 (1996).
6. Taylor, B.K., Peterson, M.A., and Basbaum, A.I. Exaggerated cardiovascular and behavioral nociceptive responses to subcutaneous formalin in the Spontaneously Hypertensive Rat. Neuroscience Letters 201: 9-12 (1995).
5. Taylor, B.K., Peterson, M.A., and Basbaum, A.I. Persistent cardiovascular and behavioral nociceptive responses to subcutaneous formalin require peripheral nerve input. Journal of Neuroscience 15: 7575-7584 (1995).
4. Taylor, B.K., and Basbaum, A.I. Neurochemical regulation of serotonin release from the rostral ventromedial medulla and its regulation by nociceptive stimuli. Journal of Neurochemistry 65: 578-589 (1995).
2. Taylor, B.K., Holloway, D.H., and Printz, M.P. A unique central cholinergic deficit in the Spontaneously Hypertensive Rat: Physostigmine reveals a bradycardia response associated with sensory stimulation. Journal of Pharmacology and Experimental Therapeutics 268: 1081-1090 (1994).
1. Taylor, B.K., Casto, R., and Printz, M.P. Dissociation of tactile and acoustic components in airpuff startle. Physiology and Behavior 49(3): 527-532 (1991)